Total Energy-Ray Flux (ERF)
against the background of all field and
physico-chemical peculiarities of the
given Earth surface
Amino acids
protein epitope
Nucleic acids
protein epitope
region (the biosphere)
Scheme-1
Formation of amino-nucleic epitope accordance (namely the accordance
between the amino acid residues and the nucleotides codones in the
Universal Genetic Code (UGC) under the influence of total Energy-Ray
Flux (ERF; including first of all solar, and terrestrial and cosmic
components), against the background of all field and physicochemical
peculiarities of the given Earth surface region (the biosphere) in
hypothetical “retranslosome”.
4
3
5
2
1
6
7
ССА-stems
Аа-tRNA
Set L-figurative
Аа-tRNA
Interior
Membrane
Organellas
Anticodones helical
sites Аа-tRNA
Polymerase activity
Nucleic Equivalent
(NE) of Epitope from
several codones
кодонов.
Fig. 1.
The variable Individual Epitope Reverse Translation (vIERT) at
the adjacent Aa-tRNA anticodon sequences.
1,2,3, … , 7 – amino acid residues of the epitope.
↯ – peptidase activity (perhaps analogical and for fig.2)
3
4
5
6
2
1
2’
7
6’
7’
1’
ССА-stems
Аа-tRNA
Set L-figurative
Аа-tRNA
Interior
Membrane
Organellas
Anticodones helical
sites Аа-tRNA
ПОЛИМЕРАЗНАЯ
АКТИВНОСТЬ
Nucleic Equivalent
(NE) of Epitope from
several codones
Fig.2.
The variable Individual Epitope Reverse Translation (vIERT) at
the adjacent Aa-tRNA anticodon sequences.
1,2,3, … , 7 – amino acid residues of the epitope
1’, 2’, 3’, … , 7’ – amino acid residues of the correspondent AatRNA complexes.
VLNS (VLNS-transfer)
Аg (Heterologous Ag)
Mcrph
Т-help
T-help
LDP
Area of tight physical contact.
Fig.3.
Hypothetical mechanisms for vIERT/VLNS-transfer possible
responsible for hypervariability in different molecules. Ag –
antigen, Mcrph. – macrophage, T-help. – T-helper cell. LDP –
Low-Differentiated Precursor in bone marrow (and possible
in thymus).
3-
А
5RNA-exon
Inverted repeat RNA-intron
Fig.4.
Formation of the double-strain hairpin structure in pre-mRNA
upon the adenosine desaminating edition. The double-strand
RNA (dsRNA) may be constituted by different elements of
cellular and viral pre-mRNA. The variant of the complementary
sequence that consists of two pieces, each containing an RNA
intron, is shown here. The loop of the hairpin is made up due to
the presence of the inverted repeat, while another part (hatched)
is formed by the intron’s fragment interacting with the premRNA exon. The adenosine residue (highlighted) is one of the
editing desamination sites in the pre-mRNA exon.
VLNS – transfer
The Genetical
RT и RTlike
activity
Polymorphism
Usual expression
Change in:
Editing:
mRNA
gRNA
U+/--
The Protein
Polymorphism
due to changes in:
NE
Hypothetical
vIERT
tRNA
mRNAs, tRNAs,
Other
kinds of
editing
rRNAs. Checkout
functional
rRNA
significance.
gRNA-like
(snoRNA) and oth.
Scheme-2
Fig. 1.
The variable Individual Epitope Reverse Translation (vIERT) at the adjacent AatRNA anticodon sequences.
1,2,3, … , 7 – amino acid residues of the epitope.
↯ – peptidase activity (perhaps analogical and for fig.2)
Fig.2. The variable individual epitope reverse translation (vIERT) at the adjacent
Aa-tRNA anticodon sequences.
1,2,3, … , 7 – amino acid residues of the epitope
1’, 2’, 3’, … , 7’ – amino acid residues of the correspondent Aa-tRNA complexes.
Fig.3. Possible mechanisms for vIERT/VLNS-tranfer responsible for
hypervariability in different molecules. Ag – antigen, Mcrph. – macrophage, T-help.
– T-helper cell. LDP – Low-Differentiated Precursor in bone marrow (and possibly
in thymus).
Fig.4. Formation of the double-strain hairpin structure in pre-mRNA upon the
adenosine desaminating edition. The double-strand RNA (dsRNA) may be
constituted by different elements of cellular and viral pre-mRNA. The variant of the
complementary sequence that consists of two pieces, each containing an RNA intron,
is shown here. The loop of the hairpin is made up due to the presence of the inverted
repeat, while another part (hatched) is formed by the intron’s fragment interacting
with the pre-mRNA exon. The adenosine residue (highlighted) is one of the editing
desamination sites in the pre-mRNA exon.
Scheme-1.
Formation of amino-nucleic epitope accordance (namely the accordance between the
amino acid residues and the nucleotides in the Universal Genetic Code, UGC, under
the influence of total Energy-Ray Flux (ERF) including solar, terrestrial and cosmic
components, against the background of all field and physicochemical peculiarities of
the given Earth surface region (the biosphere).
Scheme-2.
Possible conjunction of the hypothetical vIERT and the editing mechanisms under
the formation of the protein and genetic polymorphism.
NE – one of possible nucleic equivalents of epitope obtained as a result of a
hypothetical vIERT in one of a DNA-containing cellular structure.
VLNS-transfer – the transmission of a vector-like nucleic sequence.
Small RNAs: Trypanosome mitochondrial guiding RNAs (gRNAs) and animal
nucleolar sno-RNAs.
RT and RT-like activities are the revertase and similar activities of correspondent
cell and viral polymerase, maturase, telomerase and possibly RNA- and DNA-zymes,
and others towards short fragments of nucleic sequences.
New Hypothetical Mechanisms and Contours of The New Paradigm
Deichman A.M., Choi W. Ch., Baryshnikov An.Yu.
N.N.Blokhin Russian Cancer Research Center, RAMS, Moscow, Russia.
deichman@mtu-net.ru, amdeich@rambler.ru,
(Published: Moscow 2005, Publishing «Practical Medicine».)
Introduction
Survival of recent cellular genetic systems that keep all the biochemical
functional diversity of those metabolic machineries would be impossible without the
existence of vast groups of mechanisms maintaining both stability and variability
(plasticity as a whole) of their genomes in the state of permanent evolution. This includes
the molecular biology and enzymatic mechanisms such as replication, both kinds of
transcription, translation, various types of reparation, activity of different transposable
elements, posttranscriptional and posttranslational modifications associated with RNA
reduction, splicesome functioning, somatic hypermutation and so on. It would be
reasonable to note that the cell obligatory inherits after mitosis and/or meiosis not only a
genetic apparatus but also some others not less important apparatuses with their
characteristic components, sequences and their secondary and tertiary structure (some of
them, possibly, have been modified slightly since the age of the RNA World or even
earlier times). There is no valid expression of hereditary genetic apparatus in the absence
of these components. Each of the mechanisms mentioned functions under a relatively
strict control conditions. Moreover, each of the mechanisms has its specific level of
reliability providing reproduction, and, on the other hand, – temporary modification or a
constant mutation of genome. The processes affect both single somatic cells (much less
frequently – germ line cells) and whole organisms.
It seems possible that genetic modifications and mutations may occur not only as a
result of random mistakes and fails in the function of intracellular mechanisms (these
mistakes usually lead to the lethal outcome right away or upon activation/cell division)
and their subsequent vertical transfer (fixation in series of generations) but also under
their coordinated (coherent, multi-level) action together with some special hypothetical
(perhaps fundamental) mechanisms (Deichman, 1993; Deichman, 1997; Deichman,
Smirnov, 2003). Those recent, as well as already known, mechanisms (and multicomponent intracellular structures) have passed their evolutional pathway. They also have
their characteristic level of reliable error escape. Perhaps, at present they have become
incorporated into their whole context – with the contemporary implication of the
horizontal type of transfer as well. It is believed it was widely expanded in the early
evolutional period (Woese, 2000), particularly in purple photosynthetic bacteria (Woese,
Guptar, 1981). At the level of such mechanisms one can not exclude possible regulation
and limitation of a potentially huge number encoded and random or randomly
programmed genetic events (including temporary modification and fixed mutations) kept
by these mechanisms along with other events (first of all, the RNA editing, see below;
different kinds of reparation and others).
The given hypothesis should be open-ended, i.e. should allow step-by-step
completion along with the data accumulating in various fields of cellular biology and
other disciplines, with participation of different specialists from the adjacent fields of
research. Therefore, the mechanisms proposed by this hypothesis could be only
conventionally designated as following: (1) variable (here “variable” means multiplevalued, non-invariant; the term was offered by prof. A.M.Olovnikov), including “reverse
translation” per epitope (vIERT – variable Individual Epitope Reverse Translation) and
(2) two types of the transmission of Vector-like Nucleic Sequences. The first type,
Vector-Like Nucleic Sequence transfer (VLNS-transfer), serves for intra-/inter-cellular
exchange within the same organism. The second type, or Genetic Shuttle Feedback
system (GSF-system ≅ VLNS-transfer), is employed now into the VLNS exchange
between the cells of different organisms in the community, group of the communities of
all the three Kingdoms of Nature, including photosynthetic and non-photosynthetic space
of biosphere (Deichman, 1993; Deichman, 1997).
In the last case, probably, the whole of the both hypothetical mechanisms may be
related to the formation of environmentally balanced biodiversity in the framework of the
genetically indivisible biosphere. Those mechanisms are also capable to explain the
reasons for lack of coincidence between the different evolutionary classifications
(particularly at the comparison of those classifications for the organisms built up on the
basis of such molecules as large and small rRNAs, revertases). In contrast to the similarity
observed for different intracellular molecules currently in use for the organism
evolutionary classification, no molecule, product or function are common for all the
viruses (Maizels, Weiner 1999). Perhaps, viruses possess the ability to reproduce not only
the ancient and contemporary, but also of those replication strategies being presently
shapeding.
These reasons, possibly, are linked with the continuous competition of a number
of initial genetic systems masked by the reorganizing strata late in the evolution, those
are the elements of so-called modern united (universal – UGC) genetic code. At the
present, until the experimental confirmation of the first mechanism (vIERT), both the
hypothetical mechanisms themselves and circumstantial evidence for existence of such
mechanisms may possess the equal self-dependent value. The second mechanism has
been already partially shown, it includes: the exchange with sex gene cassettes in bacteria
and yeasts; some viruses, for example, rhabdoviruses, bunyaviruses, potiviruses, circulate
among photosynthetic and non-photosynthetic organisms revealing species- and/or tissuespecificity in relation to one or both simultaneously obligatory hosts – plants and insects;
the known role for mitochondrial plasmids in the regulation of the nucleus function upon
the formation of cytoplasmic male sterility (CMS) of plants; the resistance to drugs and
herbicides in the animal cells related to the maternal plasmid inheritance, and others
(Deichman, 1993); the natural transport of some cytoplasmic tRNAs into the
mitochondria shown in trypanosomes (and others). As the result of the experimental
electrically induced impulse puncture the high probability for the transmembrane transfer
through the mitochondrial pores for some nucleic acid sequences of cells and virusesis
observed. Such the transfer is required for intermitochondrial and nuclear-mitochondrial
exchange in relation to such processes as aging, apoptosis, cell proliferation,
mitochondrial diseases, multiple drug resistance, genome repair and maternal/paternal
mitochondrial inheritance (Zorov, 1996; Zorova et al., 2000).
1. The Mechanism for variable (polysemantic, non-invariant) “Reverse Translation”
of an Individual Epitope (vIETR-mechanism)
The first mechanism (vIERT) implies the situation when, in general, a free epitope
of 5-10 amino acid residues (including the modified low molecular weight compounds) is
converted into a primer capable to trigger some not yet uncovered special “retranslation
machinery = retranslosome” (preexisting but still evolving) functioning at least in
mitochondria and chloroplasts (perhaps, also in animal nucleus/nucleolus, where some
proteins are translated). These two organelles are relatively evolutionary autonomous and
contain all the components required for the replication and the eukaryotic cells protein
biosynthesis apparatus. The inner membranes of a mitochondrion and a chloroplast
(tilakoid) contain fractions of tRNA poorly separable even with strong detergent (Triton
X-100 and others) in severe conditions (Philippovich et al., 1987). The “retranslation
machinery” as shown below, is also a photon “hypervariable machinery” (Deichman,
2000) with inclusions of nanomolecular elements may include the ordered complex that
consists of several corresponding (Aa)-tRNAs partially fixed on a membrane. Aa-tRNAs
dimensions belong to the nanomolecular diapason and allow them to fit into the
intermembrane gap in the organelles.
There are two possible scenarios: (1) either the amino acids detach sequentially
from the epitope by peptidase activity (fig. 1) and enter into the Aa-tRNA-complexes sets
oriented by them, together with the correspondent/closely-related to them tRNAs; or (2)
the whole epitope of the amino acids (fig.2; the same peptidase activity is possible) is
capable to form and hold in its proximity a set (one or some – from a diversity lot) of not
exactly random for the given tissue (cell) Aa-tRNAs which are kept by membranous
structures. The explanation for the non-randomness is that each tissue differs by unique
metabolic (at the ATP level and others) and biochemical characteristics and the spectra of
the expressed proteins (epitopes). Though the second variant proposed earlier (Meckler,
1980; Idlis, 1980), the authors of the hypothesis about the genetic code
stereocomplementarity assumed that only the amino acids with anticomplementary
codons (respectively, the amino acids would interact with so named “anti-amino acids”)
would mutually interact first. Besides this, there was no any known specific intracellular
mechanism and localization providing a consistent integration of such a mechanism into
the general context of the molecular biology mechanisms already studied, and their
relation to the evolution of the genetic code being formed under the influence of different
(solar, terrestrial and cosmic) physical factors. However, the analysis of protein-protein
interactions (Deichman, 1996) has shown the low probability for an efficiency of the
amino acid point interactions alone, and more likely possibility for the existence of other
contacts. Further on, conformationally isolated (Zaenger W., 1987) and adjacent
anticodon areas of Aa-tRNA (or excised and ligated again; the required ligase, endo-
/exonuclease, polymerase and other activities might be provided by protein enzymes,
ribozymes, DNA-zymes) form a mini-matrix for a polymerase reaction. As the result, the
nucleic equivalent (NE , the Nucleic Equivalent ) of this epitope arises. It is assumed that
NE is of ribonucleic nature, it might be deoxyribonucleic acid as well. At the same time,
it is impossible to rule out, that such a NE (or even simple adjacent anticodon areas of
Aa-tRNA) may serve as a peculiar primer in the nucleotide-polymerase reaction within the
organelles. The primer may be either specific (in case of the NE formation for a tissuespecific epitope) leading to the expression of the tissue proteins and enzymes, or nonspecific (another variant of NE) in relation to the tissue expression – in case of induction
of the VLNS (GSF-system)-mediated transmission for other processes (see below).
The diversity of enzymatic functions is characteristic not for proteins only, but also
for discovered relatively recently cation-dependent and independent RNA-, DNA- or
hybrid RNA-/DNA-nucleozymes (Gesteland et al., 1999; Wilson, Szostok 1998; Li,
Breaker 1999). We should note that the membranes of the organelles, as known, are
permeable for some proteins and nucleic sequences, and that the presence of different
RNA-/DNA components in an autonomously replicating structure is inevitable. In case of
bacteria and archaebacteria with no cellular organelles, some similar mechanisms take
place, possibly, via the cellulal membrane (not considered here). The suggested
mechanism: (1) does not contradict to the Central Molecular Biology Dogma (CMBD),
because we do not consider the protein as a whole unit, but only its little fragment (thus,
the systems are at different levels), “not equal even to itself” for conformation sets in the
whole protein. Moreover, this mechanism assumes not the invariant (as in case of genome
expression: DNA ↔ RNA → Protein), but the variable manner of reading the
information decoding, likely related to some not yet discovered intrinsic traits of origin of
the modern UGC (Universal Genetic Code). Probably, the UGC originated
endosymbiotically from the earlier precursor codes unite into the unified code, e.g.
under conditions of the required retranslation of genetic information “from the one
code language to another” (Deichman, 1994a), at least on adjoining endosymbiotic
organelles into a cell (although something like this could take place even earlier – before
the formation of modern UGC). It is notable, however, that in both cases (fig.1 and fig.2)
the variable spectrum includes the invariant (sense- and/or antisense) NEs as a special
case – perhaps, necessary for both qualitative and quantitative regulation of the epitope
complex by means of the ratio of one or another epitopes of commonly expressed
proteins. (2) As well as most of other mechanisms, e.g. the RNA-replicative mechanism
as a part of inconsistently developing conception of the RNA World (Gesteland et al.,
1999), this mechanism, probably, has been evolved until now, when it has become
intricately incorporated (and “safely” hidden) among the other mechanisms.
It is very interesting to note that the possibility of the characteristic RNAhammerhead structures in vitro - the basic typical representatives of the RNA World
evolving structures - was experimentally demonstrated for the first time by (M.
Nashimoto, 2001) using the RNA-engineering selection assay. These structures
specifically bind to the certain amino acid (the non-bound one, or to terminal amino acid
with the similar properties) and at the same time contain the terminal codon for the amino
acid capable of the 3’ → 5’ migration onto another oligo-RNA. The author considers that
in the age of the RNA-World there was a short period of RNA/Protein symmetry, when
due to the above mentioned process the basis of both and translation and reverse
translation (of primitive proteins) was existing form. The latter one, however, after
providing a huge pool of rather necessary than random RNAs, exhausted, become
genetically dangerous (M. Nashimoto, 2001), and vanished. Our approach assumes, that
the vIERT-like mechanism still exists, and the characteristic hammerhead structures could
survive, but more could evolved into other RNA structures (including the modern
tRNAs).
It seems reasonbable that a bacteria is more close to the original ancestor variant,
however, we can not rule out that some of so-called “primitive” forms are more sensitive
to the dominating structure functional and organizational genetic innovations. From this
viewpoint, it is an enigmatic paradox that eukaryotes have more relicts of the RNAWorld than prokaryotes, which are devoided the simplicity of RNA processing (Penny,
Poole 1999). It is assumed that some RNA molecules foregoing to the protein synthesis
are existed as introns in some very early proteins. Moreover, even the evolutionary
scheme “RNA genome → eukaryote-like DNA genome → prokaryotic genome is
allowed (Poole, Jeffares, 1998). The initially requested meaning of the origin and further
maintenance of such an evolving mechanism, probably, was in the necessity for balanced
mutual orientation of the oligostructures (nucleotide and amino acid, including the
abiogenous ones) evolving together, and earlier – of their ancestors (organic and even
inorganic oligo- and polymeric structures). In this relation, we should not rule out that the
concept of the primary status of RNA-/DNA/Protein Worlds can be extended up to the
parallel inclusion each of them into the multi-step, locally subdivided, but simultaneous,
or very close in time, processes of interaction of all the three components.
The cellular vIERT mechanism may have at least two most important and partially
“calculable” usage variants.
1.1.
vIERT-mechanism and the Macrophage Mitochondria
The first version: The usage of the vIERT in the macrophage (Mcrph) mitochondria for
immunological purposes, when the antigen-mediated hypervariability in Ag-specific
receptors of B- and T-lymphocytes for hypervariable sites (CDRs) and additional
(encoded and non-encoded) jointing nucleotides in the intersegmental space V-(D)-J-C. In
some other antigen presenting cells (APC), the vIERT mechanism may be recruited for
other purposes. On the processing with the aid of the special intracellular structures
(endosomes, lysosomes, phagolysosomes, proteosomes and similar structures) the foreign
Ag presented by maccrophage is cut into the individual fragments (linear or
conformational epitopes; it is not improbable that the conformational epitopes are
stabilized by different types of crosslinks. The three different types of epitopes could be
distinguished – the “similar to own” fragments, “known foreign” fragments and
“unknown foreign” ones. In particular, the last type of fragments causes the full-value
primary specific immune response, whereas for the first two types of epitopes
corresponding clones, either activated or non-activated lymphocytes, are already present,
and initiation of this mechanism may be not required so frequently. The qualitativequantitative disbalance for the specific epitope, probably, leads to its delay at the inner,
poorly permeable even for small ions, membrane structures of the Mcrph mitochondria
causing the biochemical (finally – ATP reproduction) and the energetic (block of
proton/electron transfer – see below) failure in the function of the organelle. Such a
disbalance, probably, may be predefined by the foreign epitope and by the overexpressed
native epitope. This disbalance can specifically reflect the evolving membrane-dependent
process of the epitope sorting at the early stages of formation of the modern and ancestor
genetic systems.
Importantly, the mechanisms like vIERT and VLNS can promote (or not) the
formation of those surface antigen-specific recepto structures which at the second meeting
with epitope-(AG)-“intruder” would be able to neutralize Ag (either specifically or
nonspecifically) at the earliest stages of its spreading. Meanwhile, this mechanism of
hypervariability can be utilized not only in some normal but also conditional pathogenic
processes, in particular, at the formation of multiple variants of eluding from the immune
system cells conjointly evolving within the same host viruses causing AIDS (Deichman,
1993; Deichman, 2000; Deichman, 1994b). In this particular case, in the cell (let us
assume it as T-helper or other cell) the exogenous and endogenous VLNS (including
viruses and virus-like genetic structure), either integrated into the genome, or nonintegrated, can simultaneously meet and sometimes interact, i.e. exchange with the
genetic material, recombinate.
According to this hypothesis, due to the vIERT mechanism the NE of 15 – 30
nucleotides appears which inserts into the special VLNS. It has all the required activities ligase, endonuclease and other activities (Gesteland et al., 1999; Wilson, Szostok 1998;
Li, Breaker 1999; Deichman, 2001). Upon the close physical contact (the contact is a
known required attribute for at least of some stages of the process of immunological
maturation), the VLNS intercellular transfer (fig. 3) occurs in the chain
“macrophage → T-helper → LDP (Low Differential Precursor) between the cells. It
happens at the stage “before” the expression of the TdT-(terminal nucleotidyl-transferase)
– in the bone marrow and, perhaps, in the thymus (Deichman 1994b). The pathway in
which the low differentiated cell received the VLNS can be presented by a stem
hematopoietic cell (SHC) at either stage when the TdT-enzyme is not yet, or already (if
there are multiple stages) not expressed, we designate as the SHC-pathway.
The requirement for a close physical contact and hence, in respect to the VLNS
transfer (on the contrary, for its absence) should not be excluded for some stages of the
whole group of immunologically significant processes, such as apoptosis, activation, of
proliferation, positive and negative selection, and lymphocyte differentiation, and also
for some adhesive interactions and cytolysis (Yarilin, 1999). Tight physical contacts
(specific, non-specific and of mixed type) were observed at least for the following pairs of
cells: (1) APC – with CD8-, CD4- precursors and T-helper cells (professional antigen
presenting APC-cells are the macrophages, dendrite and B-cells; however, there are also
multiple non-professional potentially presenting APC-cells); (2) macrophages – with Th1, the other helper T-cells, cortical and stromal thymocytes, monocytes and the target
cells; (3) B-cells – with the Th2 and other helper T-cells, follicle-stimulating dendritic
cells; (4) dendritic cells – with thymocytes, T-helper cells; (5) epithelial cells (secretory,
reticular, nurse cells) – with the lymphocytes of both types; (6) Т-kill cells – with Т-help
and target cells; (7) natural killer (NK) cells – with the virus-transformed or tumor target
cells; (8) interdigital cells – with the T-cells (Yarilin, 1999). It is unlikely that we cited
the full list of events. It is obvious, that T-helper cells participate in such contacts most
frequently.
vIERT mechanism seems not to be invariant, thus the appearance of multiple NE is
possible, among which only one can be essential for the corresponding antigen structures;
this very expensive mechanism complies with the known facts (Yarilin, 1999; Royt et al.,
2000; Khaitov et al., 2000) about the mechanisms of formation of maturing and twice
selected (negatively and positively) lymphocyte clones. The possibility for the mutual
usage of mechanisms like the vIERT/VLNS transfer upon the formation of the Agspecific structures in lymphocytes was reported initially in 1962 by the author of the
clonal selection theory (Bernet, 1964; no further elaboration followed).
The author considered that in case of evolution of molecular biology conceptions
and biochemical mechanisms, as well as the revision of the CMBD, the following is
possible: (1) “the Ag fragment by some mechanism inserts into the mechanism of the
immune response in some manner”; (2) the nucleic equivalent of this fragment “is
transmitted from cell to cell as a genocopy”; finally, (3) “it is unlikely but still tempting
to assume that absolutely all the information necessary for the immune response is
preexisted (Bernet, 1964). On the contrary, it is doubtless, that the necessary mechanisms
of hypervariability (as against to the result of their activity) are preexisted. Moreover,
owing to the non-invariantness of the vIERT mechanism, the ratio of
randomness/determinism and also the ratio of instructivity (still not of the protein-protein
type)/selectivity in the immune response remains questionable: just the arms of the
balancer shifts to the new, additional, and thus, possibly, more higher level of regulation
of partially programmed and variably proceeded genetic processes. This is in consistent
with the conception of (Berg, 1922): the biological evolution is drawn rather by strict
rules than by random events, though the role of the latter ones is not excluded, but
significantly limited by such processes.
1.2 The vIERT-mechanism and Plant Chloroplasts
The second version of utilization the vIERT/VLNS-transfer mechanisms, in many
respects may be related with the chloroplasts of multicellular plants (the usage of these
mechanisms is rather related to the cytoplasmic membrane in unicellular photosynthetic
organisms; this case is not considered there). This pathway is, probably, more important
than the first one, as just at that spot those fundamentals (combination of photon, electron,
molecular and supramolecular interaction levels), which afterwards implement at the
mitochondrion level also, and at the level of some multi-component stably nonequilibrium systems and complexes, are established. It is assumed that the sensitive to the
Energy Ray Flux (ERF, in particular, the visible part of diapason, or light) photosynthetic
genome/ribosome-containing chloroplasts may be responsible both for the formation of
the itself recent universal genetic code (UGC) as well as for the diversity in its
framework.
There are some other reasons for this conclusion: (1) the genetic code is most close
related to the nuclear one in terms of universality exactly in the ERF-(including light)recipient chloroplasts, i.e. here (unlike to mitochondria) only minimal number of codons
with deviation from the standard encoding is found. It is still not clear, whether such a
deviation is a real reflection of the non-UGC codons existence at present, in the past or
an anlage for future?), or it only reveals the implication of the RNA-editing under
correction of correspondent modern UGC-genomes. However, the number of codons
being edited at the RNA level is increased rather in mitochondria, than in nuclei or
chloroplasts (Deichman, 2001). It seems reasonable that some modern mitochondrial
genetic systems are actually the naturally fixed, manifold in the past, attempts of the cell
to create the next, somewhat universal genetic code (Deichman, 1994a).
In contrast to mitochondria, there are non-reproducible by the nuclear genome
genes (up to one third from their total amount) in chloroplasts. The transcription of some
genes (e.g. psb-A photogen) and regulation of some cyclic processes in cells and whole
organisms can be initiated by light (Deichman, 1993; Deichman, 1997). (2) The number
of tRNA genes (37) in chloroplasts and quantity of their types (32) corresponds to the
same for the nucleus-encoded and functioning in the cytoplasm tRNAs, while in the
mitochondrial genomes, especially in animals and fungi, this index of intra-organelle
decoding is strictly minimized – up to nearly one tRNA per each amino acid, – although
in higher plants such minimization is less evident (Yurina, Odintsova, 1998; Kusmin,
Zaytseva, 1987). Besides this, (3) it is generally accepted that in the process of the
evolution the genetic information comes from the chloroplasts to the nucleus and
mitochondria, but not vice versa (Yurina, Odintsova, 1998).
Under the conditions of the modern UGC-encoding the protein epitope (and
hence its NE) is the smallest biochemically, immunologically, molecular-biologically and
evolutionally considerable independent unit. This results from the epitope role in multiple
recent studies. Even the smallest gene usually consists of a few hundreds nucleotides and
has distinct promoter, enhancer, intron, exon, terminal repeat and other areas, which, like
its 3’- and 5’-parts and exons, have their individual evolutional history. Since the gene
split into a great number of distinct components the NE epitope could represent the
required structure which will possess for a period of time (until another split?) the
smallest genetically significant unit.
Meanwhile, the vIERT mechanism in chloroplasts (scheme 1) may appear, first,
for a “retransmitter of a special kind” (Deichman, 1994a) – related to the translation
and adaptationn with “the language of elementary particles”, the ERF components.
Above all, this applies to different photon sets with non-equal energy level. They have
triple-source origin – solar, cosmic and terrestrial – and apparently differently
absorbing by different membrane components (metabolism each of them is genetically
predefined in common) in the numerous photosynthetic species. Then, second, the
translation from the fast-acting “quasi-particle language”( within the raw: photon,
polariton, magnon, exciton, soliton and similars)., is curried out on the surface of the
tilakoid membrane structures. At the same time, on the tilakoid surface in chloroplasts of
different photosynthetics the quasi-particle (with characteristic, individual sets of glycolipo-protein components) arise. An interaction (possibly, selective) of first particles with
the second ones occurs having in its own, partially genetically programmed generalized
profile of combined function of elementary excitation acts, relative in somewhat degree to
elementary particles. Finally, third, the “language of amino-nucleic correspondence”
formed earlier and permanently checked for the (amino acid/codon)-compliance to the
modern UGC-code, as a part of the epitope complex – “a retranslosome” – presented on
the scheme 1, is revialing. Every photosynthetic organism forms such a complex, but the
set of the initiatory ERF components in each case can be individual: the same is true also
for glico-lipo-ptotein membrane component.
By the present a vast factual and ideal material has been accumulated (of course, still
with some characteristic contradictions of the initial step) concerning the description of
possible wave characteristics and properties of biological macromolecules, their parts and
complexes (proteins , peptides, DNA/RNA-nucleoproteins and their membrane
complexes, membranes, intracellular organelles, ribosomes and so on). In this connection,
among such characteristics both related to the elementary particles (photons of UV-,
optical, IR-, X-diapasons and others) and to the quasi-particles (acoustical phonon and
others). The properties of both kind of particles, according to the opinion of some authors
(Garyaev, 1997; Chirkova, 1999), should become apparent already in the earliest (before
the appearance of any diluvial organisms) evolutionary period of formation of
autonomous genetic systems supporting the specifically oriented resonant structures and
corresponding field configurations.
Such a correspondence (Deichman, 1999) forms against the background of
different relatively strong or weak ray, field and physico-chemical factors (inside and
outside of an organelle, cell). It becomes clear that this combination is, first, unique in
total – by its unique (non-cyclic) astrophysical component, i.e. the permanent alteration
in the relative position of Earth, Sun and Stars in different galaxies and as the result of
this - the permanent general evolutionary change of the ERF itself – at least in the
visible part of the Universe take place. Second, it concerns the local-geographic,
including cyclic, component: each region of the Earth surface has its own individual set
of spatio-temporal ERF components related to the distinct position in relation to the given
area of Earth surface of the same radiative and field objects. One can conclude that the
work of the vIERT mechanism in the context of mentioned above might be initially
correlated to the “retransmission (photon-/electron-/ion-/…/supramolecular) machine”.
Some parameters related to the work of encoding sequences and reproducing by them
metabolic intermediates can be partially genetically programmed.
The support for the sorting of the epitopes occurs, probably, at the expense of the
mechanisms of interaction of the self-organizing supramolecular machineries of
“retranslosomes’. Such machineries include nanostructural elements capable to the
preliminary (even “pre-Ag-specific”) selective recognition of spatio-geometric
configuration as well as catalysis, transfer and molecular switching (Zorky, Lubnina,
1999).
Inside such dynamic complexes under the alternative adjoining of electron
envelops of their few distinct elements the structures forms periodically capable to form
the labile molecular ensembles and intermolecular low energy non-covalent bounds. We
admit that the process of electron adjoining is accompanied by blowdown of the excess
of one photon set and absorption of other photon sets – the so-called “hidden photon
firework” between the molecules and their parts. At least hydrogen, hydrophobic, ion,
van-der-waals, dipole-dipole, coordination, donor-acceptor, electrostatic and other
bounds are participated.
2. Possible Relation between Hypothetical vIERT/VLNS-transfer Mechanisms and the
Evolution of the UGC-code
The alteration in the single components of physical and physicochemical factors (ERF,
field, the factors of physicochemical and ecological micro- and macroenvironment) leads
to the changes (evolve) of amino-nucleic interacting components. These components
maintain such an interaction which, apparently, forms either the character (the number
of nucleotides per codon) of the biological genetic code or its framework diversity –
adequate to the certain stage of evolution. It is not known, whether the modern UGC is
the first (and the last in future) genetic code, but they consider that 10 evolutionary
cascades, 7 of which concord to the theory of coevolution of the UGC code and amino
acids biosynthetic pathways, may precede its formation. The theory reflects the stage,
when the physicochemical properties of amino acids are already important, though the
codons corresponding to them, like in case with Glu/Gln and Asp/Asn, can be reassigned
from the pre-amino acids to the final amino acids. With the increasing of the number of
amino acids (the canonic ones, though it is questionable, whether among the pre-amino
acids could be non-canonic ones), such an mutual correspondence becomes much more
stronger (Di Giulio 1999а).
Let’s specify some characteristic features of the UGC-code: the degeneracy; the
prevailing role for the central or the first two nucleotides in the codon at the encoding;
the usage of the same biosynthetic aminoacylation pathways for some different (though
still relative pairs, e.g. Glu/Gln and Asp/Asn) amino acids; inclusion of a number (tens)
of non-standard modified nucleotides into the RNA- and DNA-structures; the existence
of dozens natural non-standard (and in some archaebacteria – also the selenocysteine,
the standard twenty-first amino acid) non-coded amino acids; the requirement for editing
of some (numerous in the mitochondria) newly synthesized RNA transcripts, for the
splicing (including cis-/trans and alternative one) and for the posttranslational
modification; the presence of mono- and di-nucleotide coenzymes, as well as the presence
of dinucleotide preferences for some enzymes, particularly for the RNA-editing and
regular cytidine deaminases (Deichman, 2001), possessing the common evolutionary
root, and under the target-site selection (hot spots) for the RNA and DNA
modification/mutation (including different kinds of reparation); finally the existence of
autonomous non-monophyletic [as well as their tRNAs (Di Giulio 1999b)] genomeribosome-containing cellular organelles (possibly of endosymbiotic origin), one of which
is ERF-receptor (in this case photosynthesis is, probably, the way for extraction not only
the energy mainly solar energy); this list is not complete.
The organization of the genetic code is currently in the state of dynamic
equilibrium at least in relation to the surrounding metabolizing genetic systems
(including cellular and viral ones). Meanwhile, the progress of such a mutual evolution of
physicochemical peculiarities and the organization of the genetic code can be defined
together with the evolution of the dominating constellation of physical and
cosmophysical factors, i.e. in the framework of relatively open self-developing system
capable to the maintenance both – stability and plasticity of the genome. One of the
important peculiarities of such systems is, probably, the ability to maintain a stable nonequilibrium state (Bauer, 2002).
Exactly for this reason, one can assume that the code itself and its organization
were formed in several (many?) stages. The following parameters may vary during code
evolution: the number (plexity) and interchangeability (degeneracy) of both nucleotides
(including non-standard ones) in codons, and the codons themselves (including the nontriplet ones). The same applies to the possible correlation between standard and nonstandard amino acids, as well, as to the possible period of “predomination” of some of
them. Until now the nucleic acids of hundreds million (i.e. Pre-Cambrian) or milliards
years old are not found, and the ancient petrifactions (the fossils of different nature
including those older than 3 milliard years) including bacterial ones, are only the
morphological structures (pseudomorphoses), in some cases the reasons might be even
abiogenous (Gerasimenko et al., 1999).
From the evolutionary point of view, it is reasonable to assume that the
evolutionary branch towards the modern genetic systems may originate even earlier,
when only the systems with coding elements or even non-biological self-reproducing
(autocatalytic) systems existed (Gesteland et al., 1999). From this standpoint, it is
reasonable to admit that there was the period of evolution of different molecular-quantum
structures when the creating of any molecule, was probably, determined by the evolution
of interacting (“controlling”?) stable quantum structures of the cosmophysical superfluid
vacuum (“the superfluid ether – the luminiferous medium”) itself. There are oppositely
charged pairs of micro-particles (with a spin) in such a vacuum. The photons are
considered as complex stable spin-containing vortex-wave formations (related to the
Scheme 1). However, the informational mechanism regulating the inclusion of different
genomic subsystems, is still not clear (Boldyreva, Sotina, 2003); other mechanisms are
possible.
Among the variety of intermediate metabolites participating in the biochemical
reactions in the cell (there are few tens of non-standard amino acids among them) only a
little part (up to 20 – 21 amino acids) is coded by the modern genetic code (DNA), which
(as proteins and enzymes) appears to provide with the required components all the
remaining “biochemical cellular machine”. It seems to be impossible to survive, if only
the nucleic acids were inherited. Many other intracellular structures and apparatuses are
really inherited. It is unlikely to expect a long-live viable cellular offspring upon the
DNA injection into a enucleated cell of “foreign” species but not the strain .
Thus, the evolution of species and cells is not, probably, determined by the only
vertical way - the transmission of the neutrally variable genetic material in the lineage
but depends also on the definite allied intracellular structures (genome expression is
impossible without them) transmitted from cell to cell. It is not excluded also, that
evolution is connected with some special mechanisms of variably (non-invariant)
programmable variability possibly including the horizontal type of genetic material
transmission fixing by the common vertical way of inheritance later.
3. Possible Relation of Hypothetical vIERT/VLNS-transfer Mechanisms to the RNA
Editing (and other intracellular mechanisms)
Concerning the role, possible approach development, studying and correlation of
those hypothetical mechanisms with other intracellular mechanisms, the rather well-
studied phenomenon of post-transcriptional (co-transcriptional) RNA editing is of great
interest. The Only newly synthesized pre-mRNAs, tRNAs, rRNAs as well as some
introns, spacers non-identified reading frames and some others are edited. The changes
in single (as a rule, specific) and/or multiple (specific/unspecific, however not random)
nucleotides in the editing cryptogenes – both in normal and in pathologically changed
cells, including tumor cells is observed. The strategy and tactics of the introduction of
the RNA-modifications is very individual in each editing mechanism. At present, the
editing of mitochondrial RNAs has been shown most clearly, less clearly – the editing of
nuclear-encoded and viral RNAs in the nucleus and in the cytoplasm, and even less
clearly – in chloroplasts (Odintsova, Yurina, 2000). The minor transitions (А→G
changes in Drosophila nucleus and in the mitochondria of a garden snail; U→C changes
in plant mitochondria and chloroplasts and in mammalian cell nucleus), and exotic
changes [G-insertion, U → А change in the mammalian cell nucleus and UU-insertion as
well as U→А, GG→АА, А,G→U,С and C,U,G→А changes in mitochondria of different
species: mucous mould, garden snail, squid, lower fungi] and others (Deichman, 2001;
Deichman, Cheol, Baryshnikov, 2005) are obvious.
The mechanism of pausing of “halting” RNA polymerase is involved in the
phenomenon of different kinds of RNA editing (a mysterious and possibly the most
ancient form of the processing) is widely spread among many eukaryotic organisms and
viruses. In particular, at G-insertions inside short G-rich areas – the hot spots in the
paramyxovirus large purine area. This phenomenon is also observed in cellular genetic
elements: the ways and results of this process are very distinct in different species. From
the evolutionary point of view, it is particularly interesting in relation to prokaryotes
considered to be the endosymbiotic ancestors of cellular organelles. This, in turn, leads
to both intensification of scientific studies in this field as well as to the certain revision of
the essence and role of this phenomenon for the process of evolution of living organisms
(Benne 1993; Deichman, 2001). In fact, the RNA-editing enzyme was found in a
prokaryote for the first time – it was the tRNA-specific (tadA)-adenosine deaminase in E.
coli (Wolf et al., 2002). It is considered that the RNA editing is the significant part of the
process of transferring of the biological information requiring the same accuracy as
replication, transcription or translation requires.
The inscrutability of the editing is usually related to several reasons: frequently it
still requires non-evident selective advantages with the significant degree of uncertainty
of the mechanism of this non-single-step enzyme-cascade process, with the obscurity of
the final purposes (“long term plans”) of the editing. It is incomprehensible, why do the
cells prefer permanently maintain and initiate the energy-consuming “editing machines”
including those used for editing of viral mRNA transcripts seems to be purely parasitic
instead of single, either pointwise or on multiple sites at once, to introduce the nucleotide
change into the gene itself, i.e. “for a long time” (Odintsova, Yurina, 2000; Deichman,
2001).
One may consider quite an unusual feature of the gRNA-dependent “U”deletion/insertion editing its 3’→5’ direction: the DNA replication and transcription,
including reverse transcription, translation – are characterized by the reverse 5’→3’
direction. According to the results of the influence of the Ei/MAR area on the SHMs in
lymphocytes (Blanden et al., 1998; Steele et al., 1998), the putative reverse transcriptase
RT-activity required to fix the SHMs-rearranged V(D)J-genes in the mature Blymphocyte as well as their transfer into the across-barrier germ line is considered to be
also related to its 3’→5’ direction. It is not clear, can it be related to the RNA editing by
other processes.
It is supposed, that the editing of RNA originated in the age of the RNA-genome
world, under the formation of dsRNA-(double-strand)-genomes, which phylogenesis
required the substantially irreversible component to proceed the RNA→RNP→ …
evolutionary metamorphoses. In this case the RNA-relicts become steadily replaced by
proteins acting as biological catalysators concurring for the small molecules and
initiating a complex (in several steps) variant of the RNA-processing. At the same time,
proto-ribosomes, a multitude of small RNAs, pre-tRNAs, tRNA processing, the ability
for splicing (including cis-/trans- and alternative splicings), some types of editing and
others (Deichman, 2001; Jaffares, Poole 1998) are probably formed. The processing of
eukaryotic RNA including the alternative splicing and editing can generate several
distinct messages based on the same gene. As a result, the RNA pool, defined as ribotype,
varies, and possess distinct informational components: one of them is the enhanced by
editing specific ribotype. If such a ribotype is essential during a long period of natural
selection, it is supposed, to be integrated into the genome. And the eukaryotic evolution
hence is determined by the alternative ways, in which DNA and processed RNA
permanently interact (Herbert, Rich 1999).
It is assumed that between the large frequency of occurrence of changes of single
nucleotides at the RNA-level on the editing on the one hand, and the reverse mutations at
the DNA-level, on the other hand (Grienenberger 1993; Landweber, Gilbert 1993) the
relationship can occur mediated by the probable reverse transcriptase activity. However,
in this case the genetic polymorphism besides the protein polymorphism should be
revealed (for example, in relation to the petunia rsp12 protein), i.e., in particular, the level
of mutation accumulation (in the kinetoplast COIII-genes of seven trypanosome species)
in widely edited genes is much higher than in the non-edited ones. It is pretty convenient
for many authors to consider the RNA editing just as one of the internal steps in the
RNA transcription process.
At least the most clarified mechanisms of RNA editing evidently reveal the
dependency on some RNA-templates. This applies, first, to the “U”-insertion/deletion
editing in trypanosome kinetoplasts directed and straightly depended on small
mitochondrial gRNAs, and indirectly depended on the methylation by the small
nucleolar snoRNAs of mammalian cell. Second, this relates to the two types of
conversion deamination: C→U - the most frequent type of editing causing transitions in
some nuclear-coded, mitochondrial and chloroplast transcripts in higher plants, animals
and trypanosomes, and А→I (inosine) nuclear/cytoplasm editing in animals and some
viruses. Such a dependency is maintained from, correspondently: (1) mitochondrial
gRNAs, which self-renewal under the variable conditions is more than mysterious, and
snRNAs, snoRNAs (for the nucleus and nucleolus correspondingly); (2) the ssRNAs
(single strand RNAs) or rather dsRNAa in case of C→U; the intron-exon dsRNA in case
of А→I editing (fig. 4), where the informational signal in relation to the certain exon part
of the gene was the complementary part of the hairpin intron of this dsRNA (Liu,
Samuel, 1999). Regular deaminases did not manifest such a dependency.
The repeatability of the minimal size in the editing RNA areas is notable in
different species (and hence, the genetic systems also). This size is comparable to that
optimal for the epitope’s NE (the nucleic equivalent of 15 – 30 bases long). In the
mitochondrial, nuclear and chloroplast mRNAs of evolutionary distant species (from
protozoa to higher plants and animals) the newly synthesized edited fragments (so called
minimal cassettes) of 14 – 29 nucleotides long reveal: the minimal cassete size is
sufficient for the editing inside the different RNAs within the in vitro systems.
The following processes inside such cassettes not indifferent to the nucleotide
microenvironment are fixed: C→U editing (preferentially in the AU-rich areas) for the
nuclear transcripts of (1) the (the apolipoprotein-B mRNA; here the fragment of 22
nucleotides long shown the affinity to the proteins the 66 and 44 kDa of the editosome
editing complex) and (2) the chloroplast transcript genes (with formation of initiatory
AUG codon in the psbL gene, the polypeptide L in the photosystem II, and in the ndhDsubunit of dehydrogenase) genes (Deichman, 2001; Bachus, Smith 1994; Chaudhari,
Maliga 1996). Moreover, (3) the U-(less frequently) and C- (more frequently) insertional
types of editing of mitochondrial transcripts in Physarum (Deichman, 2001; VisomirskyRobic, Gott, 1997) genes were registered. It is interesting to note, that in case of Uinsertion/deletion editing of trypanosome pre-mRNA related to the implementation of so
called gRNAs. The length of the medial-informational purine-enriched (mainly with
adenine) part of gRNA itself constitutes the same value (~ 1.5 – 3 tens of nucleotides) of
the minimal cassettes (Simpson, Maslov 1993).
Recently, a dozen of studies were published (see (Deichman, Cheol, Baryshnikov,
2005)} showing the critical role of initiation step of transcription (pausing of the
“halting” RNA polymerase) in the formation of somatic hypermutations (SHM) in the
immunoglobulin molecules (Storb et al., 1998; Bachl, Ollson 1999; Winter, Gearhart
1998; Green et al., 1998). The SHM were observed in the other molecules, particulary,
in the transcriptional factor bcl-6 related to apoptosis but not in some of the
“housekeeping” genes (Storb et al., 1998). Such a dependency of the SHMs appearance
in the absence of the retardation of transcription initiation could be at least, partially,
related to the RNA editing. The RNA editing was tightly associated with the SHMs in the
Var-(here, the point mutations)- and switching Sμ-(here, the large deletions)-areas of
IgM. The CSR (class-switching recombinations) are also involved in this process. The
editing unit was the C→U deamination in AU-rich areas of the gene transcripts from the
activated B-cells from the AID-enzyme deficient mice. The AID-containing viral vectors
were tranfected in these cells (Muramutsu et al., 2000; Muramutsu et al., 1999).
Such an editing is considered to precede the regulation and catalysis of the DNAmodified step orchestrated the coordinated interaction of RNA- and DNA-levels occurs
(Kinochita, Honjo 2001). The presented on the Scheme 2 hypothetical ways and
mechanisms are just those ones capable to provide such a coordination, moreover, it can
be related to a hyper-IgM syndrome (Fuleihan 2001). An artificial system was
successfully created, in which the immunoglobulin CSRs under the influence of the AIDcytidine deaminase caused it in the fibroblasts (Okazaki et al., 2002). Normally, the
antibody (Ab) repertoire in memory B-cells and naive B-cells is different (based on the
selective characteristics and the high level of SHM in the first ones), on the other hand,
the Ab repertoire in deficient for the AID-enzyme patients it is nearly identical (Meffre
et al., 2001).
The SHM mechanism in the germinative centers of activated B-cells is not
clarified. The key role for the RNA-editing Zn2+-dependent-AID-enzyme for the
SHM/CSR processes is evident either at the RNA level, or in relation to the such further
dsDNA damage that leads to a formation of a hot spot and inaccurate function of the
DNA polymerase (Jacobs, Bross 2001; Muramutsu et al., 1999). The critical hot spot at
the SHM is considered a mutable DNA-nanomer GACTAGTAT. Nanomer contains one
of the two variants of hypermutable motif including the termination codons, serine AGC,
but not UCA codon and others - mainly in the G- and C-sites CDRs, but not the FR).
These motifs are RGYW-motif or its inverted form, the WRCY-motif, where R=A/G,
Y=C/T and W=A/T. Any changes in theses motifs decreased the SGM frequency by an
order in both DNA strands in the productively and unproductively rearranged IgVkgenes and their flunking sequences (Foster et al., 1999; Liu et al., 1997).
Transferring of the DNA nanomer 100 nucleotides above the initial position, the
SGM frequency decreased by an order (Bachl et al., 1997). The relation of such a DNA
nanomer to the RNA editing seems obvious, it was nearly fully (by its hexanucleotide
ACTAGT fragment) complemented to the DNA-variant of the anchor sequence of 11
nucleotides long (UGAUCAGUAUA) necessary for the activation of the RNA editing
deaminase at the C→U editing of the Apo-B mRNA. Here, the first four nucleotides of
the hexanucleotide are complementary to the UGAU tandem repeat, the determinative
part of the anchor sequence, and the last four themselves are its DNA-version.
Hence, in the context of stated above, the relation of the hypothetical
vIERT/VLNS-transfer the RNA editing mechanisms as well as the well or merely studied
intracellular mechanisms (replication, direct and reverse transcription, translation, repair,
splicing and others) can be represented by the Scheme 2. The scheme demonstrates the
vIERT mechanism can either precede the process of RNA editing, or even overcome it.
In the second case, both RNA and DNA levels cold be used: the mechanism related to
the RNA-(C→U)- and DNA-(dC→dU)-editing function of the AID-cytidine deaminase
is particularly important.
It was already mentioned above that in spite of some considerable advantages
(functional and genetic, essentially pheno-/genotypical plasticity) which the cell may
possess using RNA editing mechanisms, the purpose of the existence of very expensive
permanently functioning “RNA editing machinery” introducing temporary
modifications into the nucleotide composition, is not fully understood. Actually, only a
little part of the cell population (including B-cells) is often capable to be selected and
survive as a relevant to the process of the selection. However, the nature of RNA and
DNA levels interaction and the role of RNA editing in this process remains unknown. It
was also mentioned, that for the most known RNA editing mechanisms (“U”insertion/deletion, conversion C→U transitions and А→I changes) and others including
conditionally minor and exotic
editing processes is already known (on the
correspondently, gRNAs, ssRNA/dsRNA, dsRNA) or the tendency of their matrix
dependency is observed.
However, the nature of occurrence of the directing matrixes themselves
(especially for the quite fantastically powerfully self-renewing gRNAs) is unknown. The
possible informational role for introns on the dsRNA-dependent A→I editing requires
some ascertaining. The introns are classified as the most ancient, mobile and quickevolving (variable) genome fragments of DNA sequences. Such the sequences might be
the endogenous and exogenous retroposon-like or other elements with the exact NE
inside them. Exactly on this stage of events (in chapter 1.1) – the VLNS-mechanism in
the macrophage mitochondria - occurrence of the VLNS transfer is not excluded by one
of the variants of the NE-epitope (the foreign Ag) inside. From this point of view the
previously defined marsh route is overcome in the row macrophage→T-helper→LDP
(Low-Differentiated Precursor) at the stage before the expression of the TdT-terminal
nucleotidyl transferase in the bone marrow and/or in the thymus.
This means the initiation of switching on the SHC-pathway, i.e. the introducing of
some potential nucleotide (genetic) changes at the stage of very early stem cell
precursors. The epitope’s NE is delivering to the SHC into the VLNS (transposon- or
retrotransposon-like elements) capable to the integration into the genome for single or
several sites. If the integration is successful, the involvement of NE in maturation
processes Ag-specific receptors of B- and T-lymphocytes depends on Ag-inducible
processes. The named vectors (with the NE inside) can insert into the SHC-genome
during immunogenesis, or even earlier, during the lymphopoiesis, although the latter
stage is commonly considered quite an absolutely, or at least much more Agindependent. Namely, the lymphocytes are known to be potential transporters and
migrants into different, including the across-barrier organs and tissues occasionally ( the
frequent transfer into them is too dangerous to maintain the genetic stability).
The scheme 2 demonstrates that the possible role of the reverse transcriptional
processes is also considered. In the “RT-mutatorsome” hypothesis (Blanden et al., 1998;
Steele et al., 1998) the central role is reserved for this 3’→5’ process in the generation
of SHMs among immunoglobulins inside the activated B-cells, as well as in the
overcoming of cDNA rearranged variable genes including the transposon-like elements
of lymphocytes get over the germ barrier and homological recombination takes place
but with the genes of the germ line cells. The characteristic germinal configuration of Vgenes is sometimes broken by the traces of SHMs peculiar to the rearranged genes of the
mature B-cells only. This indirectly indicates the probability of such a process.
However, it is known that the whole genes are complicatedly organized structures
(for example, the 3’- and 5’- gene fragments has its independent evolutional history)
which, possibly, are assembled steadily, step by step, for a long evolutionary period. It is
impossible to exclude the possibility that into the initially split gene parts only little
sequences are included, in particular, of the one epitope’s NE length, with nonconsiderable (rather point) changes. Pseudogenes also can be a mountable-anddismountable genetic intermediate in the building of the really expressed and
polymorphous twin-genes. Possible correlation of intracellular and the cross-barrier
transfer by the “big” (cDNA rearranged V-gene transcripts) and “small” (of one NE
long) parts is hardly predictable now. The NE could be tightly associated to VLNStransporter which possibly insert into intron fragment, informational in relation to the
editing at the RNA- and DNA-level exons.
However, the degree of freedom for the smaller fragments is higher because: (1)
they might use more diverse (not only the large V(D)J fragments) VLNSs including
those specific for the process of the transfer VLNS; (2) the initial abiogenous and further
incorporated into the RNA-World/DNA-World metabolism oligostructures, which
modified concurrent evolution within the cells has probably been continued by now,
could be related more likely to the small, of one NE long, fragments. The oligostructures
themselves and their manner of metabolism inside modern cell-genetic systems scarcely
didn’t undergo considerable modification, and among the variety of potentially possible
sequences (including the prebiotic evolution stage) the random sequences unlikely could
dominate (Blumenfeld, 2002).
The enzymatic polymerase reactions with the participation of the RNAintermediate (Blanden et al., 1998; Steele et al., 1998) run with the error level by several
orders (5-6) higher than in the DNA polymerase ones (1 error per a milliard bases for
DNA). It is supposed that it could be related to the imperfection, nearly the absence of
RNA repairing systems: the DNA-repairing systems seems to be more differentiated and
powerful. Certainly, it is very problematic to overcome different systems of repair (or the
terminal replication with participation of telomerase, which is also a variant of
revertases, and it is evolutionary possible that the so-called RNA-replicases of the RNAWorld epoch are also such variants) and fix the nucleotide change even pointwise. It is
considered at present that these systems take part in the SGMs fixing as well as in
preference of the DNA-strand selection, the targets (G and C or, in case of their deficit,
A and T), the hot spots, ssDNA and dsDNA and the repair of nucleotide mismatches.
The deficit of some repairing proteins can lead to the apoptosis and even to the decrease
of the Ag-specific response and fixation, but not to the formation of SHMs in the newly
synthesized B-cell DNA (Weieserdanger et al., 2000; Kim et al., 1999; Vora et al., 1999;
Freu et al., 1998; Cascalho et al., 1998).
However, the initial uncertainty of the reactions with the RNA-intermediate
themselves can at least partially be explained not only by an repairing systems. The
mutual (alternating) or separate scheduled intervention of the mechanisms like
vIERT/VLNS-transfer and further RNA editing, i.e. the variants of the genetic processes
which are capable to program partially the limitation of choice from multitude of
random results (randomness does not disappear, it is just limited) can also occur.
Before making the final assumptions there is a need to return to the Scheme 2 and
to discuss the possible role of the RNA editing (besides the acquired by functional RNAplasticity and RNA-polymorphism) and the purpose for keeping such a very expensive
and, at the first glance, cumbersome “editing machine”. The one of same expensive
process was shown for the positive and negative selection of lymphocytes. The editing of
newly synthesized transcripts of any nature is necessary for providing the balanced
formation for two more types of polymorphism – the protein and the genetic ones.
In the first case the phenotypical, rather point, single or minimal protein
modifications take place which allow to check immediately the concurrent
successfulness of the modified versions in the context of the certain reaction or function.
In case of higher demand for kinetic and structural characteristics of such versions, the
synthesis can be enhanced of both the corresponding transcript (the analogous
characteristics of this ribotype play the same role) and the protein itself. The concurrence
between both the proteins inside the same cell as well as between the cells producing and
non-producing the modified versions, is possible. There is a need to note that not all the
molecules of a given type are necessarily exposed to editing; moreover, it could be
imperfect.
The second case: fixing the genetic modification at the level of a single cell (for
example, a B-cell), especially at the transfer to a germ-line cell (impossibility of such a
process is not proven), probably, is currying out with a retardation, and hardly occurs
independently of the level of the protein modification demand, i.e. the strength of the
inducing signal must be considered. However, the time required to fix the modification
of B- (in coded and non-coded sequences ) and germ cell can vary greatly, i.e. in the
second case the number of potential variants and evolutionary significant pathways can
affect not only the cell but also the groups of cells, tissues, organs, the whole organism
(group of organisms, society and groups of societies). It is doubtful to consider that the
whole feature is owned: it seems sensible that the small components determined by
synchronous and balanced changes and accumulation of the variety of nucleotide
changes, modifications and neutral mutations are transmitted. The neutral mutations
(being the “last drop”) sometimes gain the impression that the appearance of a whole
feature depends on a point mutation.
The mechanism of such a fixing – is the most intriguing question. Possibly,
like the complex of the DNA repair mechanisms at the SHM it occurs at least at two
stages: at the first stage the mobile structures (like VLNS) with the NE inside distribute
themselves into several distinct (or even multiple) potential docking sites in the genome
(including non-specific ones). However, the fixation of the potential changes introduced
into the sequences concerns only those ones, which are functionally essential in the
contents of the expressed and transcribed genome fragments. In terms of the earlier
publications (Deichman 1993) it corresponds to the notion of «pathway intersection
“underneath” (i.e. with participation of such processes like RNA editing, transcription
and others) and “from above” (on the entry of the NE into the nucleus as a sequence of
transposon-like or virus-like structures). The so-called “intersection of above mentioned
pathways” might be the main determinant of short-lived (in case of lymphocytes) and
long-lived ( in case of germ cells) evolutional running ones, stabilization of seconds and
the deletion of NEs of thirds from the genetic space.
Under such a scenario it is not excluded that the editing of transcripts itself points
out the possible potential character of changes in the nucleotide DNA-sequences of the
genome during the evolutionary considerable for such a genetic system period.
Moreover, (1) the DNA-level is already implicated by definition, but at this point all the
initial events could be related to the RNA-level also at the fixation of DNA-mutations in
the cell (a stem cell or a germinal one, normal or pathologically changed). At the same
time, it is not known, (2) could all this be limited to the RNA-level under the conditions
of a demand for the standard RNA-editing, i.e. in the absence of the mutations named
above. However, it seems possible that an RNA-RNA recombinational insertion (we talk
about the edited transcripts and RNA which contained NE) might be supported by
transsplicing-like processes. The appearance of several chimerical mitochondrial RNA
(the 16S mammalian RNA) might be explained by the transsplicing-like processes.
Nevertheless, such a process may occur, and it has been described in relation of the Alurepeats inserting into some genes mRNA/pre-mRNA pre-maturation (see below).
From the other hand, the recruitment of the DNA-level is possible in both
cases (1 and 2), especially considering that a latent period of hidden progress from the
intermediate DNA-variant to the final, genetically fixed and phenotypically (i.e. at the
protein or RNA-level) manifesting one could exit for each of them. At this stage the
requirement (the intensity level, tension of the threshold processes) for the editing and
hypothetical mechanisms of the vIERT/VLNS-transfer is not sufficient yet to guarantee
the final mutation and further exclusion of editing for the given site. The possibility of
the fixation of the final mutations in this period is provided with the situated nearby, or
even dispersed within the genome sequences with the NE inside. The edited sequences
could be represented by repeating elements (Morse et. al., 2002) and sequences
(Grienenberger 1993).
The Alu-repeats (of 300 b.p. long and of 1 169 291 total amount per genome)
considered to be useless genomic inclusions are the matter of interest: these are the
SINEs – the elements, ancient derivatives of the 7SL RNA-abundant cytoplasmic
component of the signal-recognizing particle mediating the translocation of the secretory
proteins through the ER. They occupy 10% of the whole human genome: 45% of them
are situated inside the genes, and the remaining ones – between the genes. The Alurepeats divides into 5 subfamilies with characteristic consensus sequences (and
conservative positions): the most ancient monomeric FAM, FRAM and FLAM and the
most ancient (80 million years old) dimeric Alu-Jo/Jb; the medium-aged (30-50million
years old), the wide-spread Alu-S (Sx, Sp, Sq, Sg, Sc); and the most recent (less than 15
million years old) Alu-Y. These repeats are characterized by the introducing of the GCsequences and by the length of the internal and terminal poly-A. It was found, however,
that the highly clustered Alu-element is not useless (they are not the “egoistic”, “junk”
DNA), and they can insert into the processing of mRNA by the splicing, the process
named “exonization”. This occurs at the expense of the splicing-like processes with the
Alu-motifs which are partially the Alu-containing introns (the terminal AG-dinucleotide
is always present). The other part is the exons of the genes of metabolism, the transport
genes and the genes signaling pathways (and – to the less extent – the part of genes of
structural proteins, oth.). More than 5% of all the alternatively splicing exons are the
Alu-derivatives, and all the known Alu-containing internal exons are subjected to the
alternative splicing (Dagan et al., 2004).
In most cases the mutations related to the constitutive exons containing Alurepeats lead to the appearance of defective genes; a selective protection is required from
the damaging Alu-insertions. Thus, for example, the Alu-derivative exon has been found
in complex with the exon of the β-glucuronidase gene in case of the moderate form of
the Sly-syndrome. Some forms of the hemophilia-A are related to the insertion of the
Alu-element into the intron-18 of the factor VIII gene. And under Hunter-syndrome the
Alu-repeats (like iduronate-2-sulphatase) mediate the unequal homologous
recombination and the genetic defect (the deletion of the exon-8). The Alu insertions can
create new and modify the existent functions, – in particular, in the gene of CK2, the
casein kinase-2, phosphorylating Ser and Thr sites of protein: the new transcript/protein
of the CK2 α-subunit was found to be highly expressed in the liver. The Alu-cassette
containing exon included the processed mRNAs with the C-terminal sequence
determining the nuclear localization of the CK-2α’-isoform was translated. The Alu-
elements were included also into the regulation of the gene expression: the repeats could
act as a repressive regulator in relation to the distally localized promoter of the CETPprotein (transferring the cholesteryl esters). Moreover, cell death (etoposide- and taxolinduced apoptosis) is related to the alternatively spliced Alu-like exon in the Bcl-ramboβ-protein. The transcripts of the ADARB1 gene (two versions of the 13-exon editing
enzyme pre-mRNA) and the exon-4 associated with the Down’s syndrome found to be
Alu-containing (chromosome 21); some other similar transcripts were demonstrated for
the chromosome 20 (Dagan et al., 2004).
In the context of the given hypothesis (Scheme 2), the following two or three
main variants of the VLNS transfer are possible: (1) the large cDNA (retrotranscripts)
transfer from either whole modified transcripts, or their truncated fragments; (2) the
transfer of small, comparable to the NE length, fragments of the nucleic sequences. In
case of the same cell – it is the simple intracellular transfer; at the intercellular transfer
into the hematopoietic cells including the stem cells (the SHC pathway) or the germinal
(across-barrier) cells, – it is substantially a horizontal transfer.
Two transfer variants (classified on the basis of the fragment length) are possible:
unfortunately, there is still impossible to exclude none of two (RNA- or DNA-)-variants
of VLNS (it depends on the intensive studing of the nucleozymes). The RNA editing
applies to both the translated and non-translated newly synthesized transcripts (and their
parts). Hence, the retaining of both possibilities is required to maintenance the continuing
concurrently balanced evolution (substantially, the pheno-/genotypic equilibrium)
historically initial for the UGC-code (and earlier – probable ancestor codes), and
contextually to the evolution of modified oligostructures.
Every transcribing fragment as the result of one or both main types of the transfer
VLNS has a chance to insert its nucleic fragment into the genome under such a retaining
process. Such a fragment, as evident from the stated above, is formed by several distinct
pathways: either as the result of the vIERT-mechanism (with or without the support of
RNA editing; see Scheme 2), or as the result of the RNA editing solely. In both cases for
the transfer of either type of ribo-VLNS the RT activity is required, and in case of
intermediate deoxyribo-VLNS-variant it is not also a single-step, but indeed the threshold
and not a short-term process of searching for the final boarding site. The discussion of the
direct retransmission of oligopeptide structure into deoxyribonucleotide oligostructure
but not into the ribonucletide despite the increasing number of publications in this is
premature. The some particular role in the presented hypothesis might play the existence
of the mechanism like the mutual (paired) DNA- (or RNA-) replication/translation
(Altshtein, Efimov, 1988; Nelsestuen 1978; other similar studies) at least as a relic
mechanism.
Obviously, the theoretical and experimental investigations of the above discussed
mechanisms could clarify the incomprehensible and intricate questions in the different
fields of the fundamental and applied biology – even in case of serious displacements of
accents.
-----------------------------------------------------------------------------------------------------------The authors express thanks to all of themes, who has accepted fissile involvement
in preparation both arguing of separate aspects and partitions of one or both parts of the
sectional publication: prof. Kolb V.A., prof. Коlesnikov А.А., prof. Gvozdev V.А., prof.
Оlovnikov А.М., prof. dr.ph.-м.s. Акsenov S.I., аcad. О.К.Gavrilov, dr.b.s. Yurina N.P.,
dr.м.s. Pavlish О.А., dr.b.s. Zhivotovsky L..А., dr.b.s.Grigorieva Е.Yu., cand.b.sc.
Vartanian А.A, and oth.
--------------------------------------------------------------------------------------------------------The popular version of the coverage of the processes, events and phenomena related to
the hypothetical mechanisms of inheritance is presented at the web site
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Abbreviation: (explanations in the text)
–
vIERT – variable Individual Epitope Reverse Translation
–
VLNS – Vector-Like Nucleic Sequences; VLNS-transfer
–
GSF-system – Genetic Shuttle Feedback system
–
LDP – Low Differential Precursor
–
ERF – Energy Ray Flux
–
ER – endoplasmatical reticulum
–
Ag – antigen
–
Mcrph - macrophage
–
Т-help (T-h) – T-helper cell
–
A, G, C, U – nucleotide bases
Abstract
In paper two new hypothetical mechanisms – variable “Reverse Translation" of
a Individual Epitope (vIERT) at 5-10 of amino acids which are flowing past at least in
rather independent genome-ribosomes containing intracell’s organellas (on interior
membranes of mitochondrions and tilacoid of chloroplasts) represented; and both
endocellular and intercellular (including cells one and various organisms of community,
group of communities, including photosynthetic and non-photosynthetic) transfer of a
Vector-Like Nucleic Sequence (VLNS-transfer) with one of variants of such Nucleic
Equivalent (NE) at 15-30 of nucleotides inside. The combination of these two
mechanisms allows is almost consistent with existing today by performances and
dogmases, but dilating them, to present contours new paradigm of a developing gene
pool of a biosphere, in which data the mechanisms appear by bound with other
endocellular mechanisms (replication, both kinds of transcription, translation, reparation,
RNA-editing, somatic hypermutation, processing, splicing etc.), and also with such
process of shaping of a genetic code, variety in his frameworks, and, even, latent
intercode retranslation ("retranslation machine = retranslosome"), which depends on
some interior both exterior to subject to evolutionary changes of physicochemical and
physical actions within the framework of unclosed autodeveloping of system with reliable
maintaining both stability, and plasticity (as a matter of fact of pheno-genotypical
equilibrium) genomes (including virus). And such retranslation, including between
genomes, means usage of various "tongues" (3 kinds: fundamental elementary particles,
quasi-particles on a surface of the relevant membranes, and, defined first by two,
naturally amino-/nucleic-acid correspondence – but in a composition hypothetical
retranslosomal epitope of a complex only). The represented mechanisms, probably,
developed from the early mechanisms-precursors of epoch of shaping primary nucleic
and peptides oligostructures and RNA-World, and to the present time have appeared
built-in in a context of modern endocellular mechanisms. The special attention is given to
possible connection with RNA-editing, somatic hypermutations and reverse trascriptional
by processes.
Keywords: variable "Reverse Translation" of a Individual Epitope (vIERT), transfer of
a Vector-Like Nucleic Sequence (VLNS-transfer), Energy-Ray Flux (ERF), intercode
retranslation (various codes and tongues), new paradigm, evolutionary changes of genetic
code, RNA-editing, somatic hypermutation, hypervariability different of nature.