Revisited to RNA/Protein symmetry
Deichman A. M. (deichman@mtu-net.ru ; amdeich@rambler.ru )
State Unitary Enterprise by N.N. Blokhin Russian Cancer Research Center, Russian
Academy of Medical Sciences (SU RCRC RAMS)
Introduction
Feasibility of some process stages for so-called “reverse translation = rT”
was demonstrated for the first time by M.Nashimoto [1]; (familiarity with this article
and the book (2005) of author namely this article is advisable). The author
synthesized special 83-nucleotide RNA (rtRNAArg), combining methods of state-ofthe-art RNA-technology and RNA-selection in vitro, using T7 RNA polymerase.
Such rtRNAArg («reverse translation RNA») simultaneously contained specific
hammerhead RNA structure with Arg-binding domain and AGG-codon (Arg) at 3’end.
Hammerhead structure contained stem/loop with 3’-end tRNA-similar
termination. Usually, the loop included 4 nucleotides (tetraloops, analogue of
proteins β-turn) whereas Arg-binding domain (UCCUCACG) contained ССU- and
ACG-trinucleotides complementary to Arg codons. It should be noted, that the
existence of rtRNA-similar structures among wide-spread different kind of lowmolecular RNAs in cells is not excluded.
As it is supposed, hammerhead-ribozyme appeared in epoch of RNA-World
(RNA-W; about 3.2 – 3.9 bln years ago) and, probably, is the predecessor for many
structural and functional components of present RNA: rRNA, tRNA, etc.
Complementary 8-nucleotide (GAGUUCCC) sequence, so-called pre-mRNA, was
synthesized in DNA/RNA synthesizer for free 5’-end single-strand portion of
rtRNAArg. Using T4 RNA, ligase pre-mRNA was covalently bound by its 5’-end with
3’-AGG-arginin codon. For control purpose both synthesized RNA were
provisionally purified by means of gel filtration.
Neo-formed 91-nucleotide duplex complex (rtRNAArg/pre-mRNA) under
certain conditions (50ºС, 10 mM MgCl2) was exposed to autonotching by С80
-2(ribozyme had only this activity). Then 11-nucleotide mRNA sequence was
disengaged from RNA-duplex. Thereby, trinucleotide AGG moved in 3’→5’
direction from rtRNAArg to pre-mRNA. Such 3’→5’ direction is characteristic at least
for ribonucleotidic synthesis with U-insertion-deletion RNA-editing in Trypanosoma
kinetoplasts, reading RNA-components of telomeres and reverse transcriptases, and
pairing nucleotides of tRNA anticodon with nucleotides of mRNA codon. But 3’→5’
directional synthesis on lagging interruptedly replicated RNA-strand is the alternative
variant: each of individual RNA fragment is synthesized in conventional 5’→3’
direction and is ligated with adjacent fragment.
Since it’s possible to create any rtRNA using the abovementioned methods,
the similar experiment can carry out for each amino acid. The author proposed the
following:
1) Evolutionary short period of maintaining RNA/protein symmetry prevailed in
evolution. This concerned primitive ribosomes when RNA and primitive
proteins were inseparably connected. RNA↔Protein-(primitive) conversions
were bidirectional, whereas accumulation of RNA-genetic information with
rT-mechanism participation was facilitated.
2) rT-mechanism requirement seceded under primarily development of proteinsynthesizing and, later, replicative apparatuses аs well as due to its
ineffectiveness and even the danger of genetic overstrain.
M.Nashimoto named the difficulties that should be overcome in hypothetical
and experimental justifications of rT-mechanism existence in the past. In
hypothetical case these are:
i) Terminal amino acid of primitive protein should behave like free acid, i.e. to
link preferably with its own rtRNA (it should be noted that early evolutional
oligofunctional organic/inorganic fixer could be replaced later by polyfunctional
bio-membrane).
ii) In order to avoid irregularity of rT-process, just terminal amino acid should be
firstly cut out from RNA-complex [(N-primitive protein-C)–(3’-AСС-premRNA)]. Secondly, partly degraded protein and partly elongated pre-mRNA
2
-3should be held by the complex (at farther action of polyfunctional apparatus is
supposed here also).
iii) Each pre-mRNA and each rtRNA, correspondingly, should have common
anchor (ССА) and complementary to anchor (GGU) sequences.
Obviously the author is exclusively oriented to universal genetic code (modern
UGC), although it is unknown whether another universal code or several/multitude
predecessor-codes or systems with coding elements were predecessors of present-day
UGC (see below).
Difficulties to be overcome for experimental justification are connected by the
author with necessity to maintain the following:
i) Covalent ligation of primitive protein with pre-mRNA (expectative remaining
relic of such process is exemplified: RNA-poliovirus is covalently linked with
VPg-protein);
ii) Exact cutting out only and exclusively C-terminal amino acid (although,
activity of multifunctional nucleoprotein complex is possible also);
iii) Permanent regeneration of eliminated 3’-codon with participation of singular
(autonotching) ribozyme activity (complex structural system action is
conceivable also).
The author associates potentiality of getting over abovementioned difficulties
with development of different RNA-engineering methods. However, even if such
solutions are found for each individual case, generally for such a scenario,
participation of some still undiagnosed special intracellular multifunctional
nucleoprotein machinery is possible. On the analogy with others (ribosome,
spliceosome, primosome, editosome) it can be named “retranslosome” (see below).
It’s clear that initially excluding existence of such natural machinery elements
in assumed RNA/protein symmetry period (and, all the more, at present)
M.Nashimoto makes the following conclusions, supposing that:
1) Over
evolutionary
significant
duration
bidirectional
(RNA↔Protein)
RNA/protein symmetry gradually degenerates (reverse-function regresses – rT-
3
-4mechanism disappears) into one-directional (RNA→Protein) movement of
biologically valuable information.
2) First primitive, than full-value cellular ribosomes are formed and later –
replicative apparatus also.
3) It’s essential to search for relics (for example, structurally-like tRNA and
elongation G-factor) of this ancient mechanism.
However, in future we’ll search for not only relics, but also rT-like mechanism
itself and some present evidences of its activity.
Among hypotheses out of “egg/chicken” series (necessary for revelation of
nucleic and/or protein biopolymers synthesis antecedence) the following are
reviewed by the author: RNA-first (RNA-W), RNP-first, Protein-first, but DNAlatter. Actually, deoxynucleotides are far harder in reproduction under pre-biotic
synthesis conditions in comparison with ribonucleotides, are more stable and
preferable for genetic information storage. Their biosynthesis (as well as DNAfragments of lagging strand and deoxysugars) in relation to ribonucleotides is
secondary. Moreover, RNA synthesis, as judged by speed (50 nucleotides per second
against 500–1000 for DNA) and replication error level (10-3–10-4 for RNA- and 10-9
for DNA-copying), is more “primitive” [2].
M.Nasimoto prefers RNA/protein symmetry, i.e. early genetic code
formation at RNA/protein parity conditions (RNP-first period). RNA-first theory is
considered to be the most developed among mentioned (see “RNA World” 1999, ed.
by R.F., Gesteland, T.R., Cech, J.F., Atkins, CSHL-Press). According to this theory
and de facto RNA molecules possess informative and many enzymic properties
simultaneously. Nevertheless, latter are less expressed than in proteins: structural
compromise inconsistency arises because of different requirements to chemical
catalysis (dynamic structures priority) and information capacity (conservative
structures priority) in the same molecule [3].
Ribozymes and RNA-World theory
4
-5Small simple ribozymes (say, autonotching/ligating hammerhead, hairpins,
HDV, VS-retroplasmids of Neurospora fungus mitochondrions, etc) are not so active
enzymes as protein ones. The latter are more flexible and abundant in ligands (of
amino acid side groups) and dehydrated Me-ion-binding sites. Hydrophobic protein
centers are more stable than RNA polar centers (with weakly hydrophobic nucleus)
open for intra-molecular interactions even in continuous dielectric medium.
Functional activity of the latter is connected with rich inclusions of several irregular
structures (stem/loop, hairpin, bulging, one-strand RNA, divergence, etc). These
structures deviate from classic A-form helix. Some of them (stem/loop, etc.) are
evolutionary oriented to interacting with proteins in RNP composition. Such like
ribozymes minimal size is 16–34 nucleotides.
For small ribozymes secondary structure as well as for proteins tertiary
structure restoration (due to hydrophobic interactions), renaturation proceeds over
several microseconds. However, small ribozymes do not need the presence of
proteins for required conformation support, whereas proteins need the presence of
RNA (inside RNP). At the same time global ribozymes are strongly hydrated even on
hidden sites. They are more linear than protein globules and restore super-helical 3Dstructure in several orders of magnitude slower (over milliseconds, seconds and even
minutes) and with larger conformation variations. Metal single-ions localization and
ribozymes catalytic sites can be different or partly overlapping. Among ions Mg2+ is
the basic ion, less frequently occur Mn2+, Ca2+ as well as di- and poly-ion sites [4-7].
Under folding conditions hydrophobic interactions for proteins and Hlinkages, generally in triads of stacking flat bases, for RNA are predominant. A
number of folding structural units interactions features proceed with involvement of
structural organized water and are determined by the balance between Van der Waals
forces (usually repulsing) and electrostatic London forces (usually attraction) having
action radius r12 and r-6, correspondingly. The RNA multiple conformational
structures is formed by 29 pairs of nucleotides whereof only 2 are Watson-Crick’s.
Just those prevail in conformational harder DNA-folding [8].
5
-6Natural ribozymes in the whole (for example I group introns) are most active
in relation to nucleic acids sequences and less to proteins, whereas proteins are most
active in relation to low molecular substrates and themselves. In both cases activity
limiting components are the transient state stability and reaction product dissociation
rate. However, both zymes species use similar catalytic strategies combinations and
exhibit other activities, but proteins have still higher catalysis specificity [6].
RNA-W theory is fairly contradictory (F., Crick: “there is the gap between
prebiotic soup and RNA-systems), and a number of different RNA-W formation
pathways can be found in different authors publications. Theory only partly answers
to the question about origin of high-level complexity protein-synthesizing and
replicative apparatuses (and accordingly of life). Origin of abiogenous and prebiotic
chirally active universal code predecessors is not clear (their number is so high that
“prebiotic life nightmare” conception is actually). It is supposed, that nucleotide and
even non-nucleotide genetic forming systems could be among them [108]. Origin of
the following is also unclear: cis-/trans-mRNA coding (splicing), functional long
coding RNA molecules from prebiotical short ribozymes, early non-template
biopolymers synthesis [4] and present-day tRNA and Aa-tRNA-synthetases [9]. It’s
of interest, that not only tRNA but also small hairpins can be synthetases substrate
[10].
Furthermore, period of RNA-W formation on the Earth (especially for initial
500 million years) and priority of single- and dipolymeric biological systems
appearance for early evolutionary stage are not clear. In general, obviously, it is naive
[108] to think that “ever-young” origin of life problem will be solved within near
decades. Moreover, RNA-W can be non-confirmable [6] whereas RNA can be not the
first single-polymer catalytic system [3]. That is why it is appropriate to study along
with other an approach assuming not only lost (as M. Nashimoto does) but factual
mechanism. Besides, it should be taken into account that verifiability of each really
existing mechanism is usually much more preferable than of a lost one.
The possibility of search for genetic code roots out of RNA-World is questioned
6
-7It is still uncertain just when and out of which predecessor, RNA or DNA
[11], LUCA, last universal common ancestor of genetic code, appeared (at least 500
million years ago). Nucleic sequences (i.e. direct evidences), age of those could be
put down for RNA-/RNP-/Protein-/DNA-Worlds epoch (billions years ago), have not
been found and, probably, will not be found using present methods. The ancient
fossils (of different nature inclusive of aged more than 3 bln years), including
bacterial, are merely morphologic structures (pseudomorphs). In some cases their
nature may be even abiogenous [12].
M. Nashimoto fairly notes (and we partly add) that:
1. Abiotic formation of several (~10) kinds of different biochemical metabolite
units could go before universal genetic code based on presently dominating
nuclear acids [13]. Or else, several (up to 10; 7 of which are in accordance with
the theory of universal code coevolution and biosynthetic pathways of amino
acids) evolutionary cascades [14]. Theory reflects the stage for which
physicochemical properties of interacting amino acids and corresponding
codons are already important. Although, codons, as in Glu/Gln and Asp/Asn
cases, can be transferred from pre-aminoacids to final amino acids without
changing biosynthesis pathway;
2. Primitive protocell contained relatively small sized RNA and proteins
molecules;
3. Each of hypotheses is considerably contradictory.
(3a) Theory Protein-first assumes self-replication not an individual molecule, as
in case of RNA-replicase of RNA-W epoch, but proteinoid complexes. Probably,
they reproduced on thermal polymerization basis (such kinds of activity:
phosphatolysis,
esterolysis,
decarboxylation,
deamination,
oxidation
and
photochemical decarboxylation, etc.) still before cell division. Notice that by now
some activities, important for self-replication of peptides groups (but non
individual ones), are virtually shown [15-17]. In 14 amino acids peptides can by
factor of 106 intensify activity of ribozymes tenfold larger in size [3].
7
-8(3b, 3c) Whereas in RNA-/RNP-first theories ribozyme auto-replication is
possible only for considerably long (at least 300-600 ribonucleotides) molecules,
the way of emergence which is fuzzily. It is even conceded that RNA-similar selfreplicating polymers existed before RNA-W epoch [18].
4. Formation of translational apparatus and genetic code is little-known;
5. Actual rT- (or like) mechanism may greatly differ from the proposed one. In
connection with such mechanism, new widely used biotechnological approach
may appear (in proteomics, molecular biology, genomics, pharmaco-genomics,
gene-informatics, metabolomics and many others).
The situation may be even more complicated if we take into account
increasing tendencies in development of studied in-vitro/in-vivo natural and artificial
DNA-zymes, chimerical DNA-RNA-zymes and their substrates. By now a significant
number of experimental works appeared where a variety of specific DNA-zymic
activities are shown. Among them are DNA- and RNA-ligasic, DNA- and RNAnotching, DNA- and RNA- nucleasic, DNA-phosphorylating and adenyling,
metallating (Н+ is substituted by Ме2+) and others. Activity of certain DNA-zymes is
comparable with the same for ribozymes and proteins [19]. On the first hand, these
activities are able to affect chemistry of some intracellular processes and individual
gene expression. Secondly, determination of these activities has increasingly
widening application in different fields: from biotechnology to therapy [19-20].
DNA-zymes activity, as well as of some ribozymes, can be induced by light
[21-22] and more expressed in relation to short oligonucleotide RNA-fragments [3,
18]. So, I group intron containing SynY-ribozyme (~180 nucleotides) Tetrahymena
preferably recognizes short (including triplet) helical oligonucleotides [18], copulates
with them and multiple reunite them (error level not above 1%). This ribozyme can
assemble autocomplementary strand from 18 fragments (~ 10 nucleotides in each).
All abovementioned leads to qualitative rethinking of the role of not only
DNA and DNA-World theory in evolution processes but also other hypotheses from
“egg/chicken” series. Each of them creates own mechanisms, as a rule, with
participation of standard nucleotides and amino acids, i.e. is exclusively oriented to
8
-9present universal code. In doing so it is not taken into account that there could be
several codes and proposed theoretical constructions, although nor fruitless, but
supposedly
premature
for
making
conclusions
concerning
“egg/chicken”
interrelation. We do not know and have no justification to think that we will know
soon from which genetic systems (or systems with coding elements) should real
counting started. Notice only that we would not look for causes giving direct or
indirect evidence of possible several codes existence but for ourselves formulated
hypothetical mechanism, one function of which can be intergenomic and/or intercode
retranslation [23-26].
Abovementioned hypotheses, including the attractive RNA-W, are
contradictory. Probably, that is why hypotheses appear in which, particularly,
processes of simultaneous DNA-replication/translation ([27-28] and RNAreplication/translation [29] are simulated. Initial (before universal code formation)
interaction of amino acids and nucleic acids (copolymerization) is supposed here. The
main but not exclusive contradiction in DNA-replication/translation hypothesis is the
following: actuation of DNA-self-replicating system formed by one/several aminoacetyl-trinucleotide progenes should be preceded by appearance of hypothetical
enzyme, progenligase. That is the protein containing 60–80 amino acids, 15-20Å in
diameter which should be able to control at least 8 (!) highly specialized functions for
copying coding him nucleotide sequence (similar analogues are not known).
However, most probably multifunctional (cellular/protocellular) complex is required
in this case.
These authors also work within universal code framework pointing at code
features giving evidence of possible primarily appearance more simple than present
UGC codes. Those are:
1) Expressed duplet (no triplet) coding: physicochemical interaction of amino
acids with first two nucleotides of DNA-codons or RNA-anticodons. In this
regard two codes are formed: pre-enzymatic (pre-biotic, including about a half
of standard and several non-standard amino acids) and modern enzymatic code.
9
- 10 2) Role-defining category of codon’s central nucleotide (relic of pre-duplet coding
existence?).
3) Existence of less hard third wobbly position in mRNA codons and in first
position of tRNA anticodons.
According to opinion of C.R., Woese [30], it is naive to believe that
physicochemical correspondence in amino-acid/codone pairing (CAP) even on early
evolution stages resolved exclusively within the framework of principle “all or
nothing”. Additional weak interactions could act as an important part also. It is
especially significant for present coding when powerful multi-component ribosomal
“pad” (including rRNA, tRNA, protein factors, etc.) is placed between amino acid
and mRNA codon.
Not known, whether several codes could be
So, all enumerated hypothesizes suppose that nothing but universal genetical
code (UGC) should be under consideration, although direct evidences of this are not
available.
Concerning discussed by M.Nashimoto theory of exterrestrial (Panspermia)
bringing-in of life (some nucleotides, amino acids, etc.) out of space [31], it seems
effective only in the presence of many other locally necessary evolution conditions,
and i.e. it does not solve the problem.
Also notice that for any mode of cell division not only nucleic acids but other
intracellular components, organelles, complex structures are obligatory inherited.
Without finding out of new evolutionary effective special mechanisms place still
remains for supporting vulgar-creation viewpoints.
Nevertheless, if such mechanism as “reverse translation” (the term is just
conditional, from below it’s evident that it’s not correct) is under consideration it’s
necessary to discuss a number of problems.
It’s essential to analyze possible
connection of the mechanism with other known intracellular genome expression
mechanisms, molecular biology central dogma (MBCD) and modern scientific
10
- 11 paradigm. It’s also necessary to consider where and how such mechanism can
proceed in a cell, why its (or the like) existence in a cell is, most probably,
unavoidable. Inevitability existence the similar mechanism will be coordinated to the
cybernetic approach within framework of which hierarchy managing and controlled
systems and subsystems various levels of organization of cells and organisms it
should be supplemented with corresponding feedbacks [113, 114]. Herewith, it is
necessary to understand that many code properties (including various stages of
genome expression) also are integral parts of modern coding method. Such properties
are obligatory connected with genetic code conception.
Then, contextually to abovementioned, we’ll name some dominant causes and
properties of the code, in connection with which genetic code could evolve, whereas
number of codes could be more than one. Such codes (with all their properties) could
possibly exist simultaneously, successively, could interact and compete, whereas
number of nucleotides in codon as well as nucleotide and amino acid compositions of
biopolymers could vary. These causes and properties are the following:
1) Code degeneracy (one amino acid – several codons, origin each whereof could
belong to differently coding systems);
2) Prevailing role of the first two (probability of duplet coding) or central
(possibility of fore-duplet coding) and decreased role of third nucleotides codon
(in tRNA-anticodon it is the first);
3) Utilization of same biosynthetic pathways of aminoacetylation for some
different, although related pairs, say Glu/Gln, Asp/Asn, Secis/Ser amino acids
(extension of genetic alphabet is possible).
4) Inclusion of great number non-standard nucleotides (over 3 tens for RNA-, and
not less than 6 variously CH3-modified their forms for DNA-structures), use of
non-standard modes of their pairing (first of all for RNA), various frequency of
codone occurrence in genes/genomes (genetic alphabet extension and, possibly,
continuing competitive regulating participation of relic forms of nucleotides
metabolism);
11
- 12 5) Existence in a cell a wide variety (over 200 accounting β-, γ-, δ-, and εvariants) of natural substandard non-coding amino acids. Some of them, not
excluded, could have polymerized properties inside early-evolutionary pre-genetic
[26] rather than present genetic systems. Furthermore, “new” amino acids are able
to mRNA-context-depending push out stop-codon. These are UGA-coding
selenocysteine (Secis; synthesized on tRNA-binded serine), UAG-coding
pyrrolisine (Pyl) and selenomethionine (Semet; supposedly UAA-coding).
However, possible role of RNA-editing (recoding mechanisms) is underexplored
here. Moreover, it’s impossible to ignore that rarely involved (less than 5–10%
amino acids) generally are not taken into account by proteinaceous chemists and
thrown off as artifact. Worded in items 4 and 5 does not exclude possibility of
potential evolutionary dynamic for coding code components;
6) For some reason modern coding does not go without some at first view
resource-spending (concerning energy, reproduction of biopolymer components of
complicated complexes, time) molecular and cellular, in point of fact searching,
processes. Searching is connected with mechanisms of genome flexibility and
cellular metabolism. Among molecular processes these particularly are: constant
editing of many newly synthesized cellular and virus RNA-transcripts; different
kinds of splicing, post-translation modifications, non-triplet translocations,
shift/overlapping reading frames, etc. These, particularly, are positive and negative
lymphocyte selections amidst cellular processes, when are reproduced unplanned
by genome separate nucleotides for synthesis of Ag-specific sites of receptors Тand B-cells;
7) Presence of single- and di-nucleotide coenzymes (NAD, FAD, etc.) as well as
specific di-nucleotide preferences for some splicing enzymes [32]. The same is
also true concerning conventional and RNA-editing cytidindeaminases [33] for
choice of recognizer and target site (hot spots) for RNA- and DNA-modifications.
Furthermore, there is an opinion about precedent existence of triplet codes based
on one (A), two (A,G), three (A,G,C) and four (A,G,C,U) letters [34];
12
- 13 8) Existence of semiautonomous monophyletic (for certain taxonomic groups) or
non-monophyletic (for other groups), as well as their tRNA [35], cellular
organelles. Latter contains own replicating and protein synthesizing apparatuses
and, probably, have endosymbiotic origin from α-proteo-bacteria and cyanobacterial progenitors in case of mitochondria and chloroplasts, correspondingly
[36]. The list is not complete.
In accordance with Orgell’s principle of continuity [108] interacting
molecules, their parts and functions clearly or latent co-evolve in a cell [37]. In the
judgment of M.Nashimoto, “reverse translation” supported biological continuity in
the past. In this regard, a pool was preserved only for those RNA which corresponded
just to claimed amino acids sequences. However, it would be premature to call such
sequences “proteins”, even primitive, as we do not know their composition and which
genetic systems they belonged to.
Our approach assumes that the RNA/protein symmetry between nucleic and
amino-acid sequences could not to disappear but to be taken over the control of a cell
to support such biological continuity. While surviving, such symmetry could support
a great number of concurrently developing and interdependent initial pre-genotypic
and pre- phenotypic processes. These processes could begin in epoch of abiogenously
demanded oligostructures of both types and can be in progress till now. Pathways for
genesis of oligostructures could be different: as a result of electrical discharge,
prebiotic СО2-fixation on the surface of pyritic crystals, interaction with clay, and
others [6].
Another (modern) variant of RNA/Protein symmetry
It’s possible to suppose the existence of a mechanism [23, 26] in cell
organelles (mitochondria, chloroplasts; more detailed below) up to present for which
protein fragment ~ 5-10 fold amino acids (epitope) orients combination tRNA nearby
itself (Fig. 1) or aminoacyl-tRNA, Aa-tRNA (Fig. 2). For this case it is supposed that
nucleotides of anticodons, at least 3 back-to-back interacting tRNA [38], approach
13
- 14 each other and form helical mini-template for polymerizing reaction (RNAdepending-RNA-polymerase, etc). It is known, that three convex anticodon
nucleotide are inside-out and each of them is recognized by 5–6 amino acids AatRNA-synthetase [39-40]. There are nonstandard ones (such as pseudo-uridine, ψ)
among nucleotides of anticodones tRNA animal and fungus mitochondria [41]. It is
also impossible to exclude participation of coding nucleotides adjacent to anticodon
as well as non-coding ones, formed as a result of tRNA-modifying (in the time of
RNA-editing) action of anticodone AI-intron [42].
For another variant (irrespective of model choice Fig. 1 or Fig. 2), not
excluded, anticodone regions can be cut out and cross-linked again (“primitive
splicing”). Necessary for this purpose ligasic, endo-/exonucleasic, proteases and other
activities become apparent by RNA-editing and translation/replication/reparation in
DNA-containing organelles (mitochondria, chloroplasts) of some organisms. Finally,
as a consequence of error, as well as a result of code degeneracy, and non-invariance
of point (1-1’, 2-2’,…, 7-7’) interactions of amino acids, amino acid of epitope can be
linked with more than one tRNA (Fig. 1) or Aa-tRNA (Fig. 2).
Unfortunately, non one of the proposed variants of vIERT-model of NE
formation (or even pre-mRNA M. Nashimoto in a context of a given hypothesis) can
not be discarded now. Especially, it is in conformity to diatropical principle of
multiplicity pathways of achievement the same result [43], in given case concerning
of huge number of evolved and variously metabolized of genetic systems.
In terms of conformation, it is important that amino-acceptor-type CCA-ends
of some 3’-cut-down upstream tRNA from mono-cistronic transcripts of overlapping
mitochondria
tRNA-genes
are
subjected
to
dynamic
posttranscriptional
transformations [44]. Meanwhile, as a result of alternate degradation and elongation
acts length of fragment with CCA-end (per 3–6 nucleotides) and included nucleotides
spectrum (CMP>AMP>UMP>GMP) of different animals are varied. However,
protection of 3’-end tRNA part from exonucleases is much more effective relating to
multiply prevailed canonic CCA-ends. Such protection is provided by aminoacylation, whereas fragment integrity restoration is provided by elongation with
14
- 15 -
4
3
5
2
6
1
7
ССА-stems
Аа-tRNA
Set L-figurative
Аа-tRNA
Inner
Membrane
Organelles
1.
2.
3.
4.
5.
Anticodones helical
sites Аа-tRNA
Polymerase activity
Nucleic Equivalent
(NE) of Epitope from
several codones
Fig. 1
кодонов.
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 one are and for Fig. 2)
15
- 16 3
4
5
6
2
1
7
6’
2’
1’
7’
CCA-stems
Аа-tRNA
Set L-figurative
Аа-tRNA
1.
Inner
Membrane
Organellas
Anticodones helical
sites Аа-tRNA
Polymerase activity
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 Aa-tRNA
complexes.
16
- 17 -
tRNA-nucleotidyltransferases (as well as by poly-adenilisation and, possibly, RNAediting) for eukaryotes, many eubacteries and some archebacteria [44]. Integrity
preservation of CCA-endings, potentially able complementary pair with two
phylogenetically conservative UGG from 23S rRNA (E. coli) is important for
ribosome’s operating in peptidyltransferase center and co-evolving, and tRNA [45].
Abovementioned features of proposed model can promote formation more than one
variant of epitope’s Nucleic Equivalent (NE) of ~ 15–30 nucleotides. Among such
NEs, in particular, can be sense- and antisens variants. In addition, NE, or even just
anticodon juxtaposed parts of Aa-tRNA, not excluded, can serve as peculiar primer
for polymerase reaction. Such NE forming mechanism can be conditionally called
variable Individual Epitope Reverse Translation (vIERT).
For the case of protein synthesis helical mRNA-template length in codonanticodon duplex region (mRNA-tRNA) does not exceed 6–9 nucleotides [9, 38].
This corresponds to two-three back-to-back oriented tRNA. In case of hypothetical
retranslosome dimension of such mRNA-tRNA continuum is not known. Holding
mechanism for epitope oriented tRNAs (Aa-tRNAs) in mitochondria and chloroplasts
[46] is known only partly (see below). Irrespective of NE formation pathway (on
juxtaposed anticodons as a template or by “primitive splicing”) polymerization of
each one-three neighboring nucleotides into integrated NE, possibly, proceeds with
pausing (specific for some RNA-polymerases). For protein synthesis distortion of
codon/anticodon interaction in ribosome A-site by different small ligands (medicines,
antibiotics, peptides, RNA-aptamers and others) may lead to minor stria displacement
of 2-3Å and wrong reading [47]. Similar hindrances are also possible for NE
synthesis as a result of vIERT.
Presumably, this (vIERT) mechanism is possible at least in mitochondria and
chloroplasts (thylakoids). Not external easily permeable for large size (up to 100 kD)
particles but internal organelle membranes hardly permeable even for small ions, fix
inseparable even in hard lysis conditions membrane-bonded tRNA-fractions [46].
17
- 18 Distance between interior and external by membranes here can reach more 100Å:
that is comparable to the maximal sizes tRNA. Probably, hypothetical vIERTmechanism in organelles, similar to protein synthesizing and replicative apparatuses,
is membrane-dependable and can function, as it is supposed, with participation of
complex retranslosome. Whereas simultaneous membrane-dependence of protein and
nucleic acids synthesis processes as well as hypothetic vIERT-mechanism in
organelles, presumably, enables admission of their conjugation [23, 26].
Cell organelles are semi-autonomous structures comprising all necessary
activities of replicative, protein-synthesizing and RNA-editing apparatuses.
Additional activities supposedly can be provided there by abovementioned RNA- and
DNA-zymes. Hypothetical vIERT-mechanism also is not being excluded for nucleus,
since not only replication and transcription are shown but tendency of some proteins
possible translation has been defined. This concerns, at least, shortened form (M246)
A→I of editing enzyme ADAR1, active in relation to transcripts of such proteintargets as GluRs, 5-HT2CR, HDV-antigen and others [48]. This enzyme localizes on
nucleolus surface and acts important role in ribosome maturation and in antivirus
protection of cell. So, ADAR1 enzyme functions turn out to be intriguingly
connected not only with RNA-editing but with its intranuclear translation [48]. For
unicellular vIERT-like mechanism can be connected with cytoplasmic membrane
(not considered).
For cell organelles of different organisms, processes of RNA-editing, provided
with different activities combination, are observed. These are ligase, endo- and exonuclease, deaminase (C→U or A→I), uridintransferase, gelicase and other editosome
activities. Special RNA-editing modes are observed in nucleus and cytoplasm, but
strategy and tactics of RNA-modifications introduction are highly individual for each
editing mechanism. Each tissue of organism has individual metabolites level, ATP,
GTP and synthesizes particular set of proteins (epitopes). That is why forming or preexisting sets of tRNAs (Aa-tRNAs) in hypothetical organelles retranslosome can be
out of chaotic.
18
- 19 Analysis of known RNA-editing modes demonstrated that the process is
directly or indirectly dependent on template-information component, whereas
transcript fragments – so-called cassettes of 14-29 nucleotides, becomes minimally
edited regions [33, 49]. Cassettes size is comparable with such for NE; (it is
interesting, that for such heterogeneous objects as the minimum size small ribozymes
– 16-34 nucleotides, miRNAs, DNA-fragments in bones and teeth of fossil exhibits,
and primers, useable in polymerase chain reaction, is similar also). The following are
reckoned among such kinds of RNA-editing: guide-RNA-(gRNA)-dependable Uinsertion-deletion editing in mitochondria of Trypanosomes; dependable on cellular
single-/double-strand RNA (ssRNA/dsRNA), cellular and virus exon-intron dsRNAstructures, correspondingly for С→U in cytoplasm and A→I deamination in nucleus
and cytoplasm.
Protein fragments (epitopes) compel attention of immunologists, molecular
biologists, biochemists, virologists, evolutionists and others. Since complex structure
and assembly of minimal genetic unit (consisting of many separate parts: promoter,
enhancer, exons, introns, terminal sequences, and having individual evolutionary
history 5’- and 3’-parts) became known the gene was split. A smaller (similar NE)
structure may turn out to be the new minimal genetic unit.
Let’s consider in short two cases of hypothetical vIERT-mechanism
application for cell organelles (mitochondria and chloroplasts). Some aspects of this
question are also represented in materials [26] more widely.
vIERT/VLNS-transfer mechanisms in mitochondries of macrophages (APK)
It is known that during the foreign antigen (Ag) processing in macrophage
(with participation of phagolysosomes, proteosomes, etc) Ag is cut up into separate
fragments, linear and conformational epitopes. The latter, not excluded, may be fixed
by different cross-linkages after damaging effect of radicals and oxygen toxic
products (under oxygen explosion). Among fragments at least three conditional types
can exist: similar to own (1), foreign known (2) and foreign unknown (3). In first two
19
- 20 cases antigen-presenting cell (macrophage, dendrite cell, another APC) cooperate the
interactions with in various degree activated T- and B-lymphocytes (including
memory lymphocytes). Meanwhile, on APC surface Ag fragments are presented
together with MHC antigens of I/II class. Thereby, usually one/few already formed
units are strengthened or weakened in development of humoral or cellular immune
responses of the whole anti-idiotypical chain.
Nevertheless, complete specific primary responses (with appearance of new
lymphocyte B- and/or T-clones) originate only in third case (new unknown foreign
epitope). This variant, not excluded, needs another scenario with the participation of
hypothetical vIERT-mechanism. Supposedly, the response can appear not only to
qualitative but quantitative (i.e. as the reply to first two fragment types too)
disbalance of epitopes subjected to membrane-depending sorting in hypothetical
retranslosome (Fig 1, 2).
Foreign Ag (epitope), probably, holds on internal membrane of macrophage
(Mcrph) mitochondria and provokes energetic and biochemical failure (level/turnover
are decreased for ATP, GTP and are increased for radicals and reactive oxygen
species). Meanwhile, proton and electron transports may be disturbed in
mitochondria normally asynchronous functioning, but in this conditionally
pathological situation synchronous [50]. Fixation of such an epitope on internal
membrane may initiate vIERT-mechanism (“protective” variant) accompanied by
deletion of epitope and reproduction of several NE variations. Newly synthesized
NEs, probably, are built in special Vector-Like Nucleic Sequences (VLNS of
transposon-/retroposon-like type) for succeeding VLNS-transfer (type of horizontal
transfer; possible physiological role of RNP/DNP with NE inside is not discussed)
between DNA-containing organelles and cells. If normal immunogenesis includes
vIERT/VLNS-transfer
mechanisms
they
can
be
used
for
generation
of
hypervariability mutually evaluating viruses (in particular, HIV; not consider).
It is known, that cellular organelles membranes are permeable for some
proteins and nucleic sequences. Analogues of intracellular and intercellular (inside of
one and between different organisms) VLNS-transfer mechanism are shown for
20
- 21 different genetic systems. This is an exchange of sexual cassettes (plasmids) by
yeasts and bacteria. Some viruses, such as rhabdoviridae, bunyaviridae and
potyviridae shuttle between photosynthetic and non-photosynthetic organisms
exhibiting species- and/or tissue-specificity relating to obligatory host, plants or
insects [51]. The role of mitochondrial plasmids is known for nucleus activity
regulation in forming the cytoplasm male sterility (CMS) of higher plants [52]. Drug
and herbicide resistance in animal cells is connected with maternally mitochondrial
plasmids transfer preferably. Natural transport is shown for several tRNA of nonsynthesized in mitochondrions trypanosomes, infecting wide range of plants,
invertebrate and vertebrate animals [49, 53]. Radio-autography was used to show
RNA flow from trophocytes to Drosophila egg [54], etc.
Moreover, for some nucleic acids sequences and viruses, high probability of
trans-membrane transfer through mitochondrial pores as a result of experimental
electrically induced impulse breakdown is shown. It is considered that such transfer
is necessary for inter-mitochondrial and nucleus-mitochondrial exchange in
connection with processes related to aging, apoptosis, cellular proliferation,
mitochondrial diseases, multiple drug resistance, intracellular particles transport,
genome reparation and parental (usually maternal, rarer paternal) mitochondrial
heredity [55-56].
It is supposed that hypervariability formation in antibodies and Ag-specific
regions of B- and T-cells receptors (BCR, TCR) proceeds with participation not only
recombination V-(D)-J-C processes but, possibly, associated to RNA-editing and
hypothetical vIERT/VLNS-transfer mechanisms. At that, lymphocytes undergo
differentiation (for B-cells it is lymphopoiesis and immunogenesis, including somatic
hyper-mutations, SHM, and class-switching recombinations, CSR). Changes in
rearranged genes of both receptors [57] are associated, inclusive of, with
incorporation of several joining, inter-segment non-coding nucleotides (of P- and Ntypes). Hypervariability (i.e. process of programmed or randomly programmed
enumeration of variants) can be formed with the participation of vIERT-mechanism.
21
- 22 Such a mechanism, presumably, takes part not only in generation but in
limitation of excess variability at Ag-specific receptor regions. Actually, number of
potentially possible receptor variants (up to 10 16 for B- and 1018 for T-lymphocytes)
by several orders of magnitude exceeds the total number of lymphocytes in animal
organism [57,109]. This variant, particularly, is affordable if nature of P- and Njoining nucleotides appearance is connected with reproduction of NEs or RNA
editing which in turn depends on reproduction of NEs (peculiar guiding minimatrixes) obtained as a result of vIERT/VLNS-transfer mechanisms exploitation
(described below).
It is known, that complete specific immune response requires close physical
contact between Mcrph and Т-helper, and Т-helper and Low-Differentiated Precursor
of hematopoietic cell (LDPhc). That is why, it is supposed [23, 58, 59], that transfer
VLNS with NE inside (Fig. 3) is carried out in the range Mcrph→Т-helper→LDPhc
(in bone marrow and, possibly, in thymus). Whole groups of cells (among those
various APC, T-cells, B-cells, epithelial, NK, target-cells, etc) come to close physical
contact by pairs. These cells participate in such immunological (and not only)
important processes as apoptosis, activation, proliferation, positive/negative
selection, lymphocyte differentiation as well as under some adhesive interactions and
cytolysis [109]. Among plurality of synthesized NEs only one/few participate in the
process of positive/negative selection of lymphocytes, on by 95%-99% subjected to
death. Herewith qualitative and quantitative characteristics of NE transferred to LDP
during VLNS-transfer may play a role of primary anti-apoptotic signals (and
formation of the certain ratio between others hemopoietic cells too).
It is of interest, firstly, the existence of vIERT/VLNS-transfer-like mechanisms
for the case of attitude to central dogma alterations was predicted by F.M.Burnet, the
author of clonally selection theory in early sixties [60]. He also considered unlikely
pre-existence of absolutely all information necessary for immune response. Another
question is that pre-existence of special response-forming mechanisms is possible,
but not ready final result. Secondly, it should be noted that vIERT-mechanism (1)
22
- 23 does not conflict with central dogma, because not a whole protein is considered but
only its small fragment having conformations combination differing from such in a
VLNS (VLNS-transfer)
Аg (Foreign Ag)
1.
2.Mcrph
3.
4.
5.
6.
Т-help
T-help
LDP
Area of tight physical contact.
Fig. 3
Hypothetical vIERT/VLNS-transfer mechanisms possible responsible for
hypervariability in Ag-specific areas immunoglobulin molecules.
Ag – antigen; Mcrph. – macrophage; T-help. – T-helper cell; LDP – Low-Differentiated
Precursor in bone marrow (and possible in thymus).
whole protein composition. Moreover (2), this mechanism assumes not invariant (as
in case DNA↔RNA→protein) but variable method decoded information reading.
But then, apparently, protein epitopes and their NEs from one side (rT-mechanism;
23
- 24 components size – nanomolecular), as well as whole (high-molecular) proteins and
genes from the other side (for translation) are elements of different-level systems
with non-identical properties. Supposedly, it may be connected with some not
disclosed as yet internal specifics of present universal code genesis and functioning
[26].
Historically, scientific works of certain authors [61-65] are concerned with
«reverse translation» problem at least; probably, it is a theme of separate paper.
Only one from these authors [64, 65] employs this mechanism in relation to protein
epitope. However, in all these works possible connection of hypothetical mechanism
with other genome expression mechanisms is not proved or even predicted (and that
was quite natural for that period of time). The same is also true in relation to
localization of mechanism in a cell and its general non-contradictory incorporation
into the entire paradigm (if it possible).
vIERT/VLNS-transfer mechanisms and higher plants chloroplasts
Application of vIERT-mechanism for mitochondria and chloroplasts can be
different in spite of some features of structural-functional, genetic and metabolic
similarity as well as community of organelles origin. Actually, the differences may be
connected at least with the fact that not more than almost strictly one tRNA for each
amino acid is found in mitochondria: for animals (2-23), fungi (7-26) and plants (2227) tRNA genes. At the same time the numbers of species (30-33) and tRNA-genes
(37) are in correspondence with the same for nuclear-coded and functioning in
cytoplasm tRNAs in chloroplasts [41, 66]. Moreover, majority of genes in
mitochondria have nuclear twins, whereas in chloroplasts up to one third of genes are
uniquely coded. Besides, there are many codons in mitochondria and few in
chloroplasts which have non-collinear to universal coding sense or are rewritten by
RNA-editing at transcriptional level. RNA editing is observed in chloroplasts much
rarely than in other cell compartments. Perhaps, it is connected with the fact that after
endosymbiotic events different kinds of nucleotide changes appeared and disappeared
24
- 25 here even much faster [26]. Finally, only chloroplasts contain light-absorbing antenna
complex of its third (thylakoid) membrane.
Light can initiate splicing (cutting-out of I and II groups introns) and
transcription of some genes (such as photosystem-2 psbA gene; without light nonspliced transcript is accumulated) and regulate certain cyclic process in cells and
whole organisms [23, 59, 67]. Analysis data for nucleotide sequences of all three
organelles homological genes enable supposition that genetic information
evolutionary movement proceeds from chloroplasts to mitochondrions and nucleus
but not in the opposite direction [68]. Causes of such directivity remain unknown, but
may be explain in context our mechanisms (see below).
It is supposed that application of vIERT/VLNS-transfer mechanisms in
chloroplasts may be the following. Scheme 1 shows process of conformity formation
between amino acids and nucleotides NE of particular epitope (Fig. 1, and Fig. 2)
inside of hypothetical retranslosome. Such conformity on chloroplast internal
membrane (in thylakoid grains region), supposedly, may form as affected by total
Energy Ray Flow (ERF; first of all it concerns flows with differing photons
combinations energy level). This proceeds against the background of all relatively
strong and weak field as well as physicochemical specifics of given Earth surface
region (biosphere). Simultaneously this conformity may reflect processes of both
universal genetic code formation (modern UGC) and diversity within its framework,
adequate to concrete evolution stage context.
ERF is composed of solar (most powerful), earth (background radiation) and
space (weak but evolutionary continuous radiation) components. For photosynthetic
organisms ERF itself evolves (unrepeatable by its spatiotemporal characteristics) in
two ways. On the first hand, in connection with absolute (acyclic) astrophysical
component: the disposition of stars, galaxies and other space objects altered relative
each other, at least in the visible part of the universe. On the second hand, in
connection with locally-geographical (including cyclic) component: roughly,
25
- 26 -
Total Energy-Ray Flow (ERF)
against the background of all field and
physico-chemical peculiarities of the
given Earth surface
Amino acids
of protein epitope
Nucleic Equivalent
of protein epitope
region (the biosphere)
Scheme 1
Formation of amino-nucleic epitope accordance
Formation of amino-nucleic epitope accordance (namely the accordance between the
amino acid residues of epitope and the nucleotides of nucleic equivalent, NE, epitope) in
the Universal Genetic Code (UGC) under the influence of total Energy-Ray-Flow (ERF)
including solar, terrestrial and cosmic components, and against the background of all
field and physicochemical peculiarities of the given Earth surface region (the biosphere)
in hypothetical “retranslosome” chloroplasts of photosynthesizing organisms.
26
- 27 combinations of photons potentially absorbable by photosynthetic organisms, for
example, at the Equator and nearby earth's Poles, obviously are not equal.
The vIERT-mechanism in chloroplasts (Scheme 1), supposedly, may act as
“the retranslator of special kind” [24, 69]. Retranslation may be connected with
translation and adaptation, firstly, “elementary particles language”, ERF components
[70]. First of all it concerns photons combinations (differing by energy levels; other
particles are not considered), supposedly, are variously absorbing by different
ingredients of membrane components of light-absorbing structures of various
photosynthetic organisms. Only, metabolism of these glico-lipo-proteid components,
generally (but not completely), clearly, is genetically determinated. Hereafter,
secondly, translation from “elementary particles language” can be carried out by
means of quickly-operating “elementary quasi-particles language” application on the
surface of chloroplasts liquid-crystal membrane structures chloroplast (thylakoids).
Among such biophysical quasi-particles, previously described for solid body, are the
following: phonon, polariton, magnon, exciton, soliton, etc [71-72].
Quasi-particles, i.e. unitary acts of exciting condensed medium, having
individual glico-lipo-proteid components combinations, appear on thylakoids surface
(nearby chloroplasts internal membranes) of certain photosynthetic organisms.
Thylakoids maturation and double layer membrane formation are closely coupled
with their components (proteins, lipids, pigments, etc) coming from or controlled by
different cellular compartments [73]. Among these compartments are nucleus,
cytoplasm and chloroplasts themselves (internal membrane, stroma). Quasi-particles
may have individual own partly genetically programmed generalized profile of total
function of unitary acts of exciting. That is why, supposedly, interaction of
elementary
particles
(photons,
etc)
with
quasi-particles
(glico-lipo-proteid
components of certain condensed medium) can be essentially selective. Finally, in the
third place, so-called “amino-nucleic conformity language” may be resulting [26], i.e.
previously formed and constantly verifiable for amino-acid/codon correspondence to
modern UGC-code, but only included in epitope complex (shown on Scheme 1) of
27
- 28 hypothetical retranslosome of chloroplasts (photosynthetic organisms). Let's notice,
that in this sense photosynthesis can appear secondary in relation to process of
formation of a genetic code.
Hereof, it is clear why vIERT-mechanism action, contextually with
abovementioned, can be initially associated with “retranslational (photon-/electron/proton-/ion-/…/supramolecular-complex)
over-molecular
machinery”.
Such
complex is formed in any photosynthetic organism; however, combination of
initiating ERF-components, as well as composition of membrane glico-lipo-protein
components, can be individual in each case.
At present, we can observe teethed tendency (not devoid of initial stage
contradictions) connected with description of possible wave characteristics and properties
of biological macromolecules, their parts and complexes. This concerns peptides, proteins,
DNA, RNA, DNP-/RNP-complexes and their membrane complexes, membranes,
intracellular organelles, ribosomes, etc. Among such characteristics it is possible to find
connected both with interaction between of elementary particles (photons of UV-, optical-,
IR-, roentgen diapasons and electrons, etc.), quasi-particles (phonon-phonon, phononexitone, etc.) and first with the second (photon-phonon, photon-excitone, etc.) under some
conditions [74, 75, 112]. Properties of either particle could begin to come out still before
appearance of any present organisms. It concerns early evolutionary stage of autonomous
genetic systems formation with maintaining of inter-oriented specific resonant structures
(particles of both kinds) and fitting with them fields configurations [26].
Epitopes (and their NEs) sorting, supposedly, proceeds in consequence of
interactions mechanisms of self-organizing supramolecular membrane-connected
nucleoprotein complexes “retranslosomes”.
Such machinery may include
nanostructure elements [76] and they are capable to preliminary selective recognition
of spatial-geometric configuration, as well as catalysis, transfer and molecular
switching. Inside of such dynamic complexes alternating collectivization of electron
envelopes of several their elements is possible. Meanwhile, there is periodical
formation of structures capable to generate labile assemblies of molecules and lowenergy
non-covalent
intermolecular
bonds.
It
is
possible
that
electrons
28
- 29 collectivization process is accompanied by downthrow of certain photons
combinations and absorption of other combinations (“latent photonic firework”)
between molecules and their parts. At least hydrogenic, hydrophobic, ionic, stacking,
Van der Waals, dipole-dipole, coordination, donor-acceptor, electrostatic and other
bonds participate in this process.
Under the hypothesis, epitopes sorting (light dependent) proceeds in
hypothetical retranslosomes of photosynthetic organisms.
In this regard, both
standard and nonstandard (new, modified old) NEs epitopes variants from unique and
conservative genome regions are reproduced. VLNS-transfer (with NE inside
VLNS), supposedly, is connected with spreading (when exceeding certain threshold
level) most strongly reproduced NEs along DNA-containing intracellular organelles
(nucleus, mitochondria, chloroplasts). It concerns cells of different organisms in all
three biological kingdoms (eukaryotes, prokaryotes, archae-bacteria) of the whole
biosphere (including its photo- and non-photosynthetic parts). Such VLNS-transfer
between cells of different organisms within community, group of communities’
organisms (involving known and unknown viruses, phages, conditional symbionts,
parasites, etc) may be called Genetic Shuttle Feedback system (GSF-system) and
concerns the various widely widespread kinds of horizontal transfer of the nucleic
information [107]. Abovementioned bunya-, poty- and rhabdoviridae, particularly,
belong to such system elements [51].
Nevertheless, NE’s pathway to intron/exon space of newly synthesized
transcript or genomes of eukaryote DNA-containing cell organelles may be not fast.
Presumably, few/multitude steps are required over evolutionary valuable period for
concrete kind of organisms (see below). As a result, nucleotide vectors (with NE
inside), probably, may spread not only vertically (from predecessors to descendants)
but horizontally (inside GSF-system, between the cells of one or different organisms,
including photo- and non-photosynthetic) too.
It is considered, that such synchronous pandemic horizontal transfer was
especially widespread in early evolution period for extraordinary mutation level. That
period is attributed to epoch of generation of collectively metabolizing fore-genetic
29
- 30 systems and unicellulars [77], particularly, purple photosynthetic bacteria [78] when
synchronously resistance to horizontal and vertical transfers was formed. Moreover,
horizontal transfer is supposed for mitochondrial (and other DNA-containing
compartments) introns of mobile I and II types between unrelated species of certain
protists as well as protists and cyanobacteria over evolutionary valuable period [79].
Possible connection of hypothetical vIERT/VLNS-trsansfer mechanisms with
RNA-editing and other genome expression mechanisms
It is supposed that vIERT/VLNS-transfer mechanisms may interact (Scheme 2)
with known intracellular genome expression mechanisms. Among those are
replication, direct and reverse transcriptions, translation, processing, splicing,
different kinds of reparation, RNA-editing, various posttranscriptional and
posttranslational mechanisms, etc. Scheme 2 first of all shows possible connection of
hypothetical mechanisms with RNA-editing process and formation of different kinds
(RNA, DNA, and Protein) polymorphisms. It is known, actually and more
potentially, the significant, if not the most part of genome (mRNA, rRNA. tRNA,
certain introns, spacers, low molecular RNA, including micro- and small
interferential RNA, and repeated regions) are transcribed as well as are edited [26]. It
is assumed that high frequency of occurrence of certain nucleotides changes on RNAlevel under editing and back mutations on DNA-level [80] may be interconnected
through reverse-transcriptase activity. However, in that case, except of protein
polymorphism, as concerning petunia protein rps12 [81], genetic polymorphism
should become apparent also. Actually, mutations accumulation level (for example,
concerning kinetoplastic СОIII-genes of trypanosome seven species) in widely-edited
genes is much higher than in non-edited ones [82]. Eukaryotic evolution, supposedly,
is governed by alternative pathways, in which DNA and processing RNA interact
permanently [83].
Phenomenon of various kinds’ RNA-editing (mysterious form of processing) is
widespread in many eukaryotic organisms and viruses. RNA-editing enzyme was
30
- 31 VLNS-transfer
The Genetical
Polymorphism
RT- and RTlike
activity
RNA
Usual expression
Change in:
editing:
mRNA
gRNA
U+/__
The Protein
Polymorphism
due to changes in:
NE
Hypothetical
vIERTmechanism
tRNA
mRNAs, tRNAs,
Other
types of
RNA
editing
rRNAs. Checkout
functional
rRNA
significance.
gRNA-like
(snRNAs/snoRNAs)
and oth.
Scheme
2
Scheme-2
31
- 32 Possible conjunction of the hypothetical vIERT/VLNS-transfer and the RNA editing
mechanisms under the formation of the Protein, RNA and DNA kinds of polymorphisms.
NE – one of possible nucleic equivalents of epitope obtained as a result of a hypothetical
vIERT-mechanism in one of a DNA-containing cellular structure (organelles).
VLNS-transfer – the transmission of a vector-like nucleic sequence.
Small RNAs: Trypanosomae kinetoplast (mitochondrial) guiding RNAs (gRNAs) and animal
nuclear/nucleolar RNAs (snRNAs and snoRNAs).
RT- and RT-like activities – the revertase and similar activities of corresponding cell and viral
polymerases (possibly RNA-zymes, DNA-zymes and others) towards short fragments of
nucleic sequences.
shown for the first time also in prokaryotes, tRNA-specific (tadA) adenosine
deaminase E. coli [84]. Mystique is associated with unobviousness of editing sites
selective advantages, considerable mechanism uncertainty and unclarity of editing
final objectives.
It is not clear wherefore cells necessarily permanently maintain and activate
high energy-consuming “editing machinery” (particularly in relation of editing
parasitic virus mRNA-transcripts). It would be much simple point-wise or over
several sites to import nucleotide changes into genes themselves “forever” [52]. It is
supposed that editing is a substantial part of biological information transfer process
requiring the same accuracy for replication, transcription, translation [33, 85].
Majority of studied RNA-editing forms need informative-matrix component.
One of NE variants, not excluded [26], may take part in its formation (see below).
Among such components at least the following may turn out to be:
1. gRNAs, easily self-reproducible and self-replicated in minicircular (probable
forefathers are plasmids) and maxi-circular DNA components for U-insertiondeletion editing in Trypanosome kinetoplasts. It is interesting, that in related
Trypanoplasma borreli gRNAs-genes are positioned at tandem repeats of
maxicurcular (200 kb) sequences [86];
2. introns, in case of А→I (sometimes C→U) editing intron/exon duplex of
hairpin dsRNA. Introns are contained in a significant part of tRNA-genes of
eukaryotes, bacteria and archaebacterias, promoting their modification and,
possibly, descend from auto-splicing introns of I and II groups or exposed
expansion of loops of molecules tRNA. In 61 (20%) from 270 known yeast
tRNA-genes small introns (14–60 nucleotides) have permanent site. The site is
32
- 33 situated over 1 base from 3’-end of tRNA anticodon stem. Deletion of these
introns by special “molecular ruler”-mechanism is associated with recognition
by endonucleases of duplex exon/intron bulge-helix-bulge-(B-H-B)-motive
with specific secondary structure [42].
Introns pertain to most ancient mobile and speedily evolving genomes
regions, are constituent and, vice versa, comprise different genes. This is a great
number of protein genes, low molecular RNA genes, and small nuclear/nucleolar
RNA included in RNP-complexes (more than 200 species; 104-106 for a cell) of most
eukaryotes cellular compartments. Nature of appearance and engagement of snRNAs/snoRNAs-genes in introns, as well as function most snRNPs (including viral) are not
known. Such specific snRNPs are involved in synthesize, assembly and maturation of
pre-rRNA/pre-mRNA, provide posttranscriptional modifications of those (hundreds
of nucleotides are methylated, pseudo-uridilated), rRNA and mRNA export into
cytoplasm. Moreover, they control spliceosomes (splicing), ribosomes (proteins
translation), and editosomes (RNA-editing). That reminds, however, snRNPsmediated genes expression control [26, 67, 87].
RNA-editing is associated with various effects: appearance and disappearance
of sense and stop/start codons; conservatism and hydrophobicity enhancement for
protein fragments after transcripts editing; participation in unifying "rewriting" of
genes of mitochondria (are more often) and chloroplasts for nucleus [52,88].
Furthermore, RNA-editing is able to: regulate splicing (for example, length of mRNA
apolipoprpotein-В transcript: ApoB-100→ApoB-48, etc), shift of reading frame
(mRNA, ORF); activate nuclease reactions for virus protection (say for C→U and
A→I hyper-editing); provide repair on RNA- and modifications on DNA-levels, etc
[26,89]. The reason and the mechanisms of maintaining such a resource-consuming
mechanism are not completely clear yet. So, for example, certain site editing
observed for some species may be absent in homological transcripts for related
species. In this case DNA-site often contains “necessary” nucleotide, and editing is
not required [82, 90]. But it is still not known which developments (events) were
predecessors of that.
33
- 34 For vIERT-mechanism (Fig. 1, Fig. 2) appearance of oligoribonucleotide NE
is most likely. Such NE in composition of retroposon-like VLNS may be integrated
but then eliminated or fixed by one/few sites in coding/non-coding (including
repeated sequences) part of genome (nucleus, mitochondria, chloroplast). The same,
but less likely, is in case of NE deoxyvariant reproduction also. Hypothetically
deoxy-NE may develop due to some known or unknown proteins (or nucleozymes)
reverse-transcriptase activity. Reverse transcriptase related domains contain certain
telomerases, maturases, and nucleotidyltransferases. Homology blocks with seven
viral reverse transcriptases were found in mitochondrial genome ascomycetes [41].
RT-activity existence corresponds to the hypothesis of pan-edited
mitochondrial cryptogenes (Trypanosome kinetoplasts) substitution for their whole
with cDNA-versions retroposing into nucleus. Also it is consistent with the fact of
trans-kinetoplastidia
of
low-copy-number
mini-circular
DNA
into
nucleus
(mechanism is unknown) under conditions of artificial isolation of cellular structures
[86]. Moreover, that is in partial correspondence with the fact of reverse transcription
of monomer-length plasmid transcripts (with 3’-ССА-end tRNA-like terminals) of
Neurospora
spp.
fungus
containing
replicating
Mauriceville
and
Varkud
retroplasmids in mitochondria [91]. Both cases of VLNS fixation (with NE ribo- or
deoxy-variants) in genome may have not fast consequences and appear then in any
form (RNA, DNA, Protein) of cell polymorphisms.
Hystohematic barriers of ordinary parenchymal and overbarrier (hematoencephalic, germinative, transplacental) tissues differ strongly. All tissues show at
least minimal permeability concerning certain virus, and sometimes, cellular
(lymphocyte, etc) agents. Australian authors [92, 93] observed modified germinal
configuration (deletions/insertions of individual or several nucleotides) of
immunoglobulin genes in gamete genomes of many vertebrates.
Based upon these and circumstantial evidence, authors assumed that
modifications
could
be
the
traces
of
rearranged
V-(D)-J-fragments
of
immunoglobulin genes integration. Whereas integration itself was a result of transfer
retro-copies of such fragments from hyper-mutated lymphocyte and their following
34
- 35 homological recombination with corresponding allelic sequences of gamete haploid
genome. Fixation of hyper-mutational phenotype in B-lymphocyte itself was also
connected with homological recombination of retro-transcript, but under conditions
of intracellular transfer variant. In accordance with our vision, however, VLNStransfer could concern rather shorter nucleic fragment (including NE length) too and
be connected not only in concrete B-lymphocyte, but also with low-differentiated
precursors of stem hematopoietic cells (LDPhc, see above), further differentiating in
various directions including lymphocyte line.
Furthermore, site-specific ectopic transfer of mitochondrial yeast II group
intron into unrelated RNA by means of reverse splicing is described [67]. That is
why, not excluded, ribo-VLNS (with NE inside) can be incorporated into exon-intron
space of newly synthesized edited transcripts under trans-splicing-similar process.
RNA-RNA-integration under the recombination conditions provides appearance of
chimaera’s mitochondrial RNA, particularly 16S RNA of certain animals [94].
Likewise exons 1 and 2 (from different transcripts of psaA gene photosystem I
plastids of certain algae) are connected; low-molecular RNA of tscA-gene are
involved in this process [36, 95]. Such similarity also concerns “exonization introns”
mechanism known in respect of Alu-repeats incorporated into maturating pre-mRNA
of certain genes [96].
Various repeated sequences which common share composes major portion of
eukaryote genome are interesting in many ways. Alu-repeats, for example, can move
into intron/exon space and modify genes functions [96]. Mysterious gRNA-genes
responsible for pre-mRNA-editing [86] are localized in tandem-repeated maxicircular kinetoplast sequences of some protozoan (Trypanoplasma borreli, etc).
Telomerase RNA-component reverse-transcription provides chromosomes with
tandem-repeating telomeric repeats. Spliceosome effectiveness and specificity is
often associated with di-, tetra-, penta-, hexa- as well as 74-nucleotidic repeats [87].
In repeated sequences of so-called “junk-DNA” of human origin [97] up to 99% of
variable sites (out of their 3 million total number) are detected.
35
- 36 The role of repeated sequences in genome expression is gradually
reconsidered. Not excluded, that some of them may turn out to be one of possible
sites of NEs primary localization (“depot”). Repeats consensus variants may form
from similar but not identical NEs. In turn evolution of many genes, in particular
snRNAs/snoRNAs-genes, contained in repeats and introns of protein-coding genes,
as well as corresponding snRNPs functions may be dynamically associated with
reproduction of repeats consensus variants. Concepts of possible relationship between
genetic code evolution, protein’s and nucleic cell components (including introns and
repeating sequences) co-evolution and rT-similar mechanism already exist [61].
For integration of NE into transcript we have a case of RNA- or RNA/Protein- polymorphisms. Herewith, fast check for functional value of introduced
modifications is possible (Scheme 2). Functionally more significant the modified
protein-versions can assure preferential synthesis of respective transcripts. The
functional value of modifications is also checked in non-translated RNA (rRNA,
tRNA, etc). Probability of retro-transcription for modified whole (large portions)
transcripts and their succeeding integration into DNA-genome is not equal to zero,
although it is not high under reverse splicing of certain mitochondrial introns in fungi
I group. Moreover, subsequent horizontal transfer of introns between cells and
organisms is considered possible also [67].
The combination of interactions at RNA-(first) and DNA-(later) levels, in
particular, is shown for Zn2+-dependable activation-induced cytidindeaminase (AID)
in lymphocytes germinative centers (corresponds to Scheme 2). AID but not Apobec1 cytidindeaminase is active during of SHM formation, gene conversions and CSR in
immunoglobulin of activated B-lymphocytes and fibroblasts as well as in some other
genes and cells [98]. Under super-expression of these enzymes in E. coli (both are
members of RNA-editing cytidindeaminase mammalian family) induced DNAmutations. AID-enzyme is able both to edit RNA and to modify DNA
immunoglobulin
(DNA-editing
model). Transcript
is
edited
in
anchoring
UGAUCAGUAUA sequence region whereas DNA-modification in mutable
GACTAGTAT-nanomer region. There is linkage between these sequences: the part
36
- 37 of nanomer, ACTAGT-hexanucleotide, is complemented to UGAUCA-part of
abovementioned (UGAUCAGUAUA) anchoring sequence [26, 99-103].
Modifying effect of AID-enzyme is also supposed with regard to homological
IgV-genes of gp120-coding region env-gene hyper-mutative HIV-1 virus [104]. HIV1 hypermutations in chronically infected cell cultures are preferably associated either
with C→U modifications under RNA-editing [105] or reverse transcription low
accuracy [106] for long-infected cultures.
Thus, the hypothetical vIERT/VLNS-transfer mechanisms, probably, can
realize in three ways (Scheme 2). The first way is realized only at RNA-level: RNAor RNA- and protein’s polymorphisms are formed. Second way: only at DNA level.
Under formation of genes polymorphism NE (consensus variant) pathway in genome
may run through its entry firstly into repeated sequences (Alu, oth.), low-molecular
RNAs-genes (including miRNAs, siRNAs, oth.) and/or later into intron/exon space of
asymmetrically replicated DNA complementary main or lagging strands. In
particular, the transcription factors and reciprocal genetic networks of expression
with participation miRNAs is regulated [110]; in turn, NE
s can take part as in formation miRNAs genes (for the evolutionary period) and
expression them, as and in a competition with miRNAs for linkage with 3'-regions of
mRNA-targets (by inhibition of translation, RNA degradations). For different
genome regions (coding, non-coding), genes (immunoglobulin, “household”, etc) and
cells (somatic tissues, germinative, lymphocytes) such pathway and speed of sitespecific NE fixation, obviously, may not coincide.
Over evolutionary valuable period, however, combination of both pathways
with potential formation of all three polymorphism’ types is more probable (Scheme
2). This requires, presumable, several stages separated by time and site of action for
interacting on RNA- and DNA-levels components in different genetic systems. It is
unlikely, that these stages coincide for ontogenesis and phylogenesis of individual
organism, as well as for more complicated exchanges of genetically valuable material
Possible connection of hypothetical mechanisms with some mechanisms of
genes/genome expression and biological processes
Hypervaria-ty and joint
evol cell/vir fragm genomes
(norm/pathol; program 37
partition variants)
- 38 -
Macroevolution? (point
Microevolution?
Genome Evolution,
adaptations [point mutat
structural genes, block
reorganizations; more
likely for intraspecific
changes; [vIERT (NE
"from below") + VLNStransfer].
Genes
Expression
Mechanisms
(means miRNAs,
oth.)
mutation regulator genes,
large block reorganize-ns genome/chromosomes, horizontal transfer, oth. (ecosystems
biosphere: new taxons → new
species). (Possible"crossing"
ways "from below"/"from
above": vIERT + GSF-system
(synchronous VLNS-transfer
to various biological species).
Ecology, the Biodiversity, Food
chains.
RNA-Editing: use
dsRNA-matrix:
gRNAs, A→I, C→U.
Effects:splicing, rise
hydroph/conservatism
proteins, shift framework, unification genes, antivir protect,
change stop/start/sens
codones, oth.
Mechanis inter-
Hypothetical mechanisms
(vIERT/VLNS-transfer,
vIERT/GSF-system)
genome/intercoding (Nucl,
Mt, Chlrpl),
retranslation.
Phenogenotipical
balance. Polymorphism (on Prote-
Epigenesis
in, RNA, DNA level).
Genetical and
Epigenetical
Non-coding protein exons
parts genome (repeats; introns;
aspects of
pathology.
Synchron dynamic maintenance of conservatism in
various genomes [vIERT +
Horizontal transfer (=GSFsystem)].
Potencial changes in : gRNAs,
different small RNAs, repeats,
introns, exons, rRNAs, tRNAs,
immunoglobulin (BCR, TCR, oth.)
molecules families.
rRNAs, tRNAs, various smRNAs,
gRNAs, oth.)
Formation Gen Code/Variety in its
frameworks (modern photosynth
organisms). New ratio theor RNA-/RNP/DNA-/Protein-Worlds (latent proceeding
evolution oligostructures). Cooperating
"Languages": Elementary-/Qusielementary-particles, AA/Codone (in
structure epitope/NE complex
"retranslosome").
Scheme №3.
Scheme-3
Possible connection of hypothetical mechanisms with some mechanisms of
genes/genome expression and biological processes
38
- 39 in populations and between different organisms of ecological communities.
Moreover, all abovementioned concerning vIERT and VLNS-transfer (GSF-system)
mechanisms, supposedly, do not exclude their effective (competitively coordinated)
of participation in evolution of individual genomes and synchronous processes of
micro-/macroevolution in ecological-connected communities [107]. Both processes,
however, may be depending from different combinations vertical and specific
horizontal methods of transmission and fixation of genetic information. The proposed
approach can explain some of the reasons of non-coincidence of different phyletic
classifications also.
In conclusion we shall result the Scheme 3 reflecting opportunities of
perspective analysis for prospective connection of hypothetical mechanisms with
group of known/unknown of gene expression processes and mechanisms [111].
Among
them
there
are,
at
least,
following:
formation
of
hypervariability/conservatism in oligonucleotides fragments of genome (including
coding/non-coding a parts of genomes) at various biological species; RNA editing;
formation of various kinds of polymorphisms (phenogenotipical balance); formations
of a genetic code and a variety in its frameworks (including intergenomic/intercoding
kinds of retranslation); genetic/epigenetic changes and pathologies; processes of
microevolutions of genomes and macroevolutions of organisms.
Acknowledgment: Author thank d.b.sc.N.P. Yurina, prof. V. A. Kolb and prof. V.A. Gvozdev
for valuable comments and good advice сoncerning article and on the future; c.b.sc.
A.A. Vartanian for help in correcting the MS.
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