Linking Cell Cycle Reentry and DNA Damage in
Neurodegeneration
The MIT Faculty has made this article openly available. Please share
how this access benefits you. Your story matters.
Citation
Kim, Dohoon, and Li-Huei Tsai. “Linking Cell Cycle Reentry and
DNA Damage in Neurodegeneration.” Annals of the New York
Academy of Sciences 1170 (2009): 674-679. Web. 1 Dec. 2011.
© 2009 New York Academy of Sciences
As Published
http://dx.doi.org/10.1111/j.1749-6632.2009.04105.x
Publisher
New York Academy of Sciences
Version
Final published version
Accessed
Thu May 26 09:57:20 EDT 2016
Citable Link
http://hdl.handle.net/1721.1/67340
Terms of Use
Article is made available in accordance with the publisher's policy
and may be subject to US copyright law. Please refer to the
publisher's site for terms of use.
Detailed Terms
INTERNATIONAL SYMPOSIUM ON OLFACTION AND TASTE
Linking Cell Cycle Reentry and DNA Damage
in Neurodegeneration
Dohoon Kim and Li-Huei Tsai
Howard Hughes Medical Institute, Picower Institute for Learning and Memory,
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology,
Cambridge, Massachusetts, USA
Aberrant cell cycle activity and DNA damage have been observed in neurons in association with various neurodegenerative conditions. While there is strong evidence for a
causative role for these events in neurotoxicity, it is unclear how they are triggered and
why they are toxic. Here, we introduce a brief background of the current view on cell
cycle activity and DNA damage in neurons and speculate on their relevance to neuronal
survival. Furthermore, we suggest that the two events may be triggered in common
by deregulation of fundamental processes, such as chromatin modulation, which are
required for maintaining both DNA integrity and proper regulation of cell cycle gene
expression.
Key words: cellular activity; neurodegeneration; DNA damage
Aberrant Cell Cycle Activity
in Neurodegeneration
Aberrant neuronal expression of numerous
cell cycle proteins, such as cdc2, cdk4, cyclins B1 and D, p16, and Ki-67, were observed in Alzheimer’s disease (AD) brains over
10 years ago, as covered in previous reviews.1,2
In addition to aberrant expression of cell cycle
genes, neurons in AD brains can undergo DNA
replication activity, as evidenced by DNA incorporation of the thymidine analogue bromodeoxyuridine, and extra copies of some chromosomal loci. This collective phenomenon, often
referred to as cell cycle reentry, is both unexpected and perplexing, considering that most
of these neurons have been terminally differentiated during development and had been quiescent for decades. The cell cycle activity appears
to be abortive, and actual division of neurons
has not been observed.
Address for correspondence: Li-Huei Tsai, PhD, Picower Professor of
Neuroscience, Picower Institute for Learning and Memory, Department of
Brain and Cognitive Sciences, Investigator, Howard Hughes Medical Institute, Massachusetts Institute of Technology, 43 Vassar Street, Cambridge,
MA 01239. Voice: 617-324-1660; fax: 617-324-1657. lhtsai@mit.edu
Aberrant cell cycle activity has been reported
in other neurodegenerative contexts as well.
For example, expression of cell cycle proteins,
such as proliferating cell nuclear antigen and
E2F transcription factor 1 (E2F-1) and DNA
synthesis, has been observed in postmortem
Parkinson’s disease (PD) brains and in a mouse
model of PD.3 Aberrant cell cycle activities have
also been reported in amyotrophic lateral sclerosis (ALS),4 Huntington’s disease (HD),5 and
ischemia.6
DNA Damage in
Neurodegeneration
DNA is constantly subjected to damage,
such as chemical modifications (for example
8-oxoguanine, a type of oxidative DNA modification) as well as single- and double-strand
breaks. These can arise endogenously from attack by intracellular metabolites (such as reactive oxygen species) or through errors during
DNA replication (e.g., stalled replication fork),
or exogenously through exposure to carcinogens or irradiation. DNA damage poses a threat
to metazoans as it can cause mutations ranging
International Symposium on Olfaction and Taste: Ann. N.Y. Acad. Sci. 1170: 674–679 (2009).
c 2009 New York Academy of Sciences.
doi: 10.1111/j.1749-6632.2009.04105.x 674
Kim & Tsai: Cell Cycle Reentry and DNA Damage
675
from base pair changes to chromosomal
translocations to even aneuploidy, which can
result in neoplasticity.7
There has been a steadily accumulating body
of evidence of damage to DNA in various
neurodegenerative conditions, since first suggested over two decades ago.8 For example,
upregulation of DNA strand breaks in neurons have been reported in AD9 and HD,10
while increased 8-oxoguanine lesions have been
reported in ALS11 and ischemia.12 Damage
to mitochondrial DNA has been reported
in PD.13
Interestingly, it was demonstrated that oxidative DNA damage accumulated in the human
brain with age, and could be responsible for the
gradual loss of neuronal function observed with
old age.14 As neurodegenerative diseases, such
as AD, PD, and ALS are highly age-dependent,
this finding raises the possibility that accumulation of DNA damage constitutes the elusive
“age component” that may trigger, contribute
to, or permit neuronal pathogenesis.
inhibition of cell cycle machinery, for example
through cdk inhibitors, has been shown to be
protective against neurotoxic insults, such as ischemia and kainate-induced excitotoxicity.20,21
There is also significant evidence for an active role for DNA damage in neurodegeneration. The importance of DNA integrity in neurons is exemplified by congenital conditions,
such as ataxia telangiectasia, xeroderma pigmentosum, Werner syndrome, and Cockayne
syndrome, in which the underlying genetic defect is in genes that are involved in DNA repair.22 In these conditions, following relatively
normal brain development, progressive and severe neuronal death is observed, demonstrating
that maintenance of DNA integrity is a requirement for neuronal survival at the postdevelopmental stage. Furthermore, it is established that
neurons are highly susceptible to toxicity from
DNA damaging agents, such as camptothecin,
etoposide, and hydrogen peroxide.23
Relevance of Neuronal Cell Cycle
Activity and DNA Damage in
Neurodegeneration
Thus, both aberrant cell cycle activity and
DNA damage in neurons are observed during the progression of multiple neurodegenerative conditions. An important issue is whether
these play a causative role in neuronal death or
are simply parallel phenomena observed during neurotoxicity. The collective evidence supports an active role for cell cycle activity and
DNA damage in neuronal death.
Expression of cell cycle proteins has been
reported as a predictor for neuronal death,
for example in AD postmortem brains and
in a mouse model displaying neurodegeneration.15,16 In addition, overexpression of oncogenes or cell cycle proteins, such as SV40 large
T antigen, c-myc, or E2F-1, which drive cell cycle activity, has been shown to be toxic to neurons in vivo and in culture.17–19 Furthermore,
Why Do Aberrant Cell Cycle
Activity and DNA Damage Occur in
Neurons, and Why Are These
Events Neurotoxic?
In metazoans, maintaining proper control
of cell cycle activity and DNA integrity is
paramount for preventing neoplasia. This is especially relevant in actively proliferating cells,
and is reflected in the high level of “evolutionary investment” in terms of complex cell cycle
related machinery and robust DNA damage repair/response mechanisms found in these cells,
as reviewed previously.7 It is important to note
that cell cycle control, DNA damage, and cancer are intricately interlinked in the context
of cycling cells. Multiple checkpoints and tumor suppressor mechanisms, such as p53, act
to halt cell cycle progression if DNA damage is
detected. Conversely, DNA damage is an important trigger for mutagenesis and chromosomal rearrangements, and subsequent alterations in oncogenes or tumor suppressor genes
can elicit uncontrolled cell cycle activity and
676
cancer. Importantly, as an antineoplastic safeguard, cells that have excessive DNA damage
and/or attempt to progress through the cell cycle while harboring DNA damage will be eliminated through apoptosis.7
In contrast, neurons are postmitotic and
highly differentiated, and it would appear at
first glance that cell cycle activity and DNA
damage would have limited relevance and consequence, especially compared with actively
proliferating cells. Interestingly, neurons appear to have decreased baseline levels of certain types of DNA repair processes, possibly reflecting decreased demand for DNA repair due
to absence of cell cycle activity and decreased
risk of neoplastic consequences.24,25 Decreased
repair capacity combined with the inherently
high metabolic rate of neurons (and increased
byproducts that can damage DNA) may lead to
accumulation of DNA damage over time. This
process may be exacerbated or accelerated in
neurodegenerative conditions, such as AD.
Thus, accumulation of DNA damage may
reflect an evolutionary strategy where energy
expenditure is invested toward neuronal function rather than DNA integrity.25,26 On the
other hand, it is more difficult to resolve the underlying purpose for aberrant cell cycle reentry
in neurons. Perhaps, as discussed below, aberrant cell cycle activity in neurons may be better viewed as neglected/lost suppression of cell
cycle activity (and cell cycle gene expression)
rather than an active purposeful event, in a similar manner to neglected DNA maintenance.
A remaining question is why DNA damage
and cell cycle activity are toxic to neurons. From
an evolutionary point of view, even differentiated cells may still have some capacity to form
neoplasia. For example, while the expression of
oncogenic SV40 large T antigen can trigger
neuron death,17 some groups have successfully
immortalized differentiated neuron-like cells by
overexpressing this gene.27,28 Thus, if DNA
damage is combined with aberrant cell cycle
activity, namely S phase, it may still be prudent
for the organism to eliminate these neurons via
programmed cell death. At the very least, this
Annals of the New York Academy of Sciences
neuronal cell death may represent a leftover effect of antineoplastic safeguards that are critical
in cycling cells.
Along these lines, it has been hypothesized
that both DNA damage and cell cycle activity
are required to trigger apoptosis in adult neurons in neurodegenerative conditions.25 It has
been observed that neurons can tolerate certain
types of DNA damage without triggering cell
death. However, it is predicted that DNA damage coupled with cell cycle activity will potently
trigger checkpoint responses that will induce
neuronal death.25 In support of this notion,
neuroprotective effects of inhibiting genes with
checkpoint function, such as p53 and ataxia
telangiectasia mutuated (ATM), have been reported.29,30
Linking Cell Cycle Reentry and DNA
Damage in Neurodegeneration
As discussed, cell cycle reentry and DNA
damage are features of multiple neurodegenerative conditions that may act in concert to
trigger neuronal death. However, only recently
has a link between the two phenomena been
suggested in the context of neurodegeneration.
It was reported that DNA damage can induce
cell cycle reentry in primary neurons.29 Furthermore, DNA damage and cell cycle reentry have been observed concomitantly in culture and mouse models displaying neuronal
death,31,32 although these are not necessarily
linked to common neurodegenerative conditions, such as AD.
Cyclin-dependent kinase 5 (Cdk5) is a nonconventional cdk that is primarily active in
postmitotic neurons and is hyperactivated following accumulation of its regulatory binding
partner p25, during neurodegenerative conditions, such as AD and stroke.33,34 We have
previously described an inducible p25 overexpression model that displays several features of
AD including neuronal death, amyloid beta upregulation, tau hyperphosphorylation and neurofibrillary tangles, and cognitive decline.35–37
Kim & Tsai: Cell Cycle Reentry and DNA Damage
677
In this model, we observed that both cell cycle
activity and double-stranded DNA breaks occur in neurons, in a highly associated manner
both spatially and temporally.38
How are DNA damage and cell cycle reentry
linked? A likely contributing factor is that one
may positively impact on the other. As mentioned, DNA damage can trigger neuronal cell
cycle activity and death, but paradoxically, in
a checkpoint-dependent manner.29 Conversely,
cell cycle activity, in particular DNA replication
activity, in neurons may cause DNA damage. It
is known that S phase is a period of particularly
high susceptibility to DNA strand breaks, for
example through stalling or collapse of replication forks.39 At a molecular level, tumor suppressor/DNA damage response genes may link
aberrant cell cycle activity and DNA damage.
For example, ATM and p53 can serve as DNA
damage checkpoints and suppress cell cycle activity in response to DNA damage, but can also
activate DNA repair mechanisms.7 Thus, loss
of function of such genes is often associated with
DNA damage and loss of DNA integrity in proliferating cells. Interestingly, loss of function of
ATM in ataxia telangiectasia causes progressive
neurodegenertion.22
Another possibility is that both aberrant cell
cycle activity and DNA damage can be triggered by deregulation of fundamental cellular
processes that are required for both DNA integrity and proper control of cell cycle gene
expression. An intriguing candidate process is
altered chromatin modulation and transcriptional deregulation, which is already known to
be relevant in the context of neurodegenerative
disease.40,41
In eukaryotes, nuclear DNA is wrapped
around histone octamers, which collectively are
referred to as nucleosomes, the basic unit of
chromatin. Modifications to histones, such as
acetylation and methylation, affect the degree
of DNA/histone affinity and internucleosomal
affinity, resulting in “open” and “closed” (or
“silent”) loci of chromatin.42 DNA at these open
loci is highly accessible to molecules that interact with DNA, including transcription factors
and DNA damaging agents. Thus, through effects on DNA accessibility, the regulation of
chromatin plays an important role in a variety
of processes in the cell.
Alteration of chromatin can affect cell cycle
activity through altered expression of genes involved in the cell cycle. For example, opening
of chromatin leading to increased transcription
of cell cycle machinery can drive cell cycle activity, or conversely, increased expression of cell
cycle inhibitors can inhibit cell cycle in proliferating cells.43 Differences in effects may depend
on the specific loci that are affected as well as
the cellular context. In the case of adult neurons, deregulation of chromatin, in particular
opening of cell cycle gene loci that are normally
maintained as silent, may result in aberrant cell
cycle gene expression and cell cycle activity.
Furthermore, open chromatin loci are
thought to be more accessible to DNA damaging agents.44 For example, it has been
shown that inhibition of histone deacetylases
(HDACs), which leads to hyperacetylation of
histones and opening of chromatin, renders
DNA hypersensitive to damaging agents, such
as gamma and UV irradiation.45 Furthermore,
chromatin modulation is involved in DNA
repair.46
Thus, as tight regulation of chromatin is
thought to play a role in a wide range of cellular
processes,42 regulation of this process may elicit
deleterious consequences which include deregulation of cell cycle activity and loss of DNA
integrity. We recently uncovered a pathological
pathway which supports this notion. In the p25
overexpressing model for neurodegeneration,
p25/Cdk5 inhibited HDAC1 activity, resulting
in aberrant cell cycle activity and formation of
DNA double strand breaks, and neurodegeneration.38 HDAC1 inactivation-induced cell cycle protein expression appears to be a direct result transcriptional derepression, while
further studies are required to ascertain how
HDAC1 inactivation results in double-strand
breaks. This study demonstrates that neurotoxic stimuli can impact chromatin regulation
to cause neurodegeneration. Other chromatin
678
Annals of the New York Academy of Sciences
References
Figure 1. A conceptual overview of cell cycle
reentry and DNA damage in neurodegeneration.
In neurodegenerative conditions, such as stroke or
Alzheimer’s disease, a neurotoxic insult (e.g., excitoxicity or amyloid beta) is speculated to activate a common trigger mechanism, for example aberrant modulation of chromatin loci. This perturbation could trigger cell cycle activity through desilencing of cell cycle
related genes, and DNA damage though enhanced
access of DNA to DNA damaging agents. The combination of damaged DNA and the detection of DNA
damage by checkpoints that have been activated by
the aberrant cell cycle activity will induce neuronal
death through checkpoint-triggered apoptosis.
modulators that potentially may be deregulated
in neurodegenerative disorders and other diseases include the other HDACs and histone
methylases/demethylases.
In conclusion, the purpose and underlying
mechanisms of neuronal cell cycle activity and
DNA damage are still poorly understood phenomena, but they likely work in concert to
induce neuron death in multiple neurodegenerative conditions. A general overview of the
process is outlined in Figure 1. The identification of common underlying mechanisms may
have important therapeutic implications.
Conflicts of Interest
The authors declare no conflicts of interest.
1. Raina, A.K. et al. 2000. Cyclin’ toward dementia:
cell cycle abnormalities and abortive oncogenesis in
Alzheimer disease. J. Neurosci. Res. 61: 128–133.
2. Neve, R.L. & D.L. McPhie. 2006. The cell cycle as a
therapeutic target for Alzheimer’s disease. Pharmacol.
Ther. 111: 99–113.
3. Hoglinger, G.U. et al. 2007. The pRb/E2F cell-cycle
pathway mediates cell death in Parkinson’s disease.
Proc. Natl. Acad. Sci. USA 104: 3585–3590.
4. Ranganathan, S. & R. Bowser. 2003. Alterations in
G(1) to S phase cell-cycle regulators during amyotrophic lateral sclerosis. Am. J. Pathol. 162: 823–835.
5. Pelegri, C. et al. 2008. Cell cycle activation in striatal
neurons from Huntington’s disease patients and rats
treated with 3-nitropropionic acid. Int. J. Dev. Neurosci.
26: 665–671.
6. Hayashi, T., K. Sakai, C. Sasaki, et al. 2000. Phosphorylation of retinoblastoma protein in rat brain
after transient middle cerebral artery occlusion. Neuropathol. Appl. Neurobiol. 26: 390–397.
7. Sancar, A., L.A. Lindsey-Boltz, K. Unsal-Kacmaz &
S. Linn. 2004. Molecular mechanisms of mammalian
DNA repair and the DNA damage checkpoints. Annu.
Rev. Biochem. 73: 39–85.
8. Robison, S.H. & W.G. Bradley. 1984. DNA damage
and chronic neuronal degenerations. J. Neurol. Sci. 64:
11–20.
9. Adamec, E., J.P. Vonsattel & R.A. Nixon. 1999. DNA
strand breaks in Alzheimer’s disease. Brain Res. 849:
67–77.
10. Anne, S.L., F. Saudou & S. Humbert. 2007. Phosphorylation of huntingtin by cyclin-dependent kinase 5
is induced by DNA damage and regulates wild-type
and mutant huntingtin toxicity in neurons. J. Neurosci.
27: 7318–7328.
11. Ferrante, R.J. et al. 1997. Evidence of increased
oxidative damage in both sporadic and familial
amyotrophic lateral sclerosis. J. Neurochem. 69: 2064–
2074.
12. Hayashi, T., M. Sakurai, Y. Itoyama & K. Abe. 1999.
Oxidative damage and breakage of DNA in rat brain
after transient MCA occlusion. Brain Res. 832: 159–
163.
13. Zhang, J. et al. 1999. Parkinson’s disease is associated with oxidative damage to cytoplasmic DNA and
RNA in substantia nigra neurons. Am. J. Pathol. 154:
1423–1429.
14. Lu, T. et al. 2004. Gene regulation and DNA damage
in the ageing human brain. Nature 429: 883–891.
15. Busser, J., D.S. Geldmacher & K. Herrup. 1998. Ectopic cell cycle proteins predict the sites of neuronal
cell death in Alzheimer’s disease brain. J. Neurosci. 18:
2801–2807.
Kim & Tsai: Cell Cycle Reentry and DNA Damage
679
16. Herrup, K. & J.C. Busser. 1995. The induction of
multiple cell cycle events precedes target-related neuronal death. Development 121: 2385–2395.
17. al-Ubaidi, M.R., J.G. Hollyfield, P.A. Overbeek & W.
Baehr. 1992. Photoreceptor degeneration induced by
the expression of simian virus 40 large tumor antigen
in the retina of transgenic mice. Proc. Natl. Acad. Sci.
USA 89: 1194–1198.
18. Konishi, Y. & A. Bonni. 2003. The E2F-Cdc2
cell-cycle pathway specifically mediates activity
deprivation-induced apoptosis of postmitotic neurons. J. Neurosci. 23: 1649–1658.
19. McShea, A. et al. 2007. Neuronal cell cycle re-entry
mediates Alzheimer disease-type changes. Biochim.
Biophys. Acta. 1772: 467–472.
20. Park, D.S., A. Obeidat, A. Giovanni & L.A. Greene.
2000. Cell cycle regulators in neuronal death evoked
by excitotoxic stress: implications for neurodegeneration and its treatment. Neurobiol. Aging 21: 771–781.
21. Katchanov, J. et al. 2001. Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and
activation of cell cycle machinery before delayed neuronal cell death. J. Neurosci. 21: 5045–5053.
22. Rolig, R.L. & P.J. McKinnon. 2000. Linking DNA
damage and neurodegeneration. Trends Neurosci. 23:
417–424.
23. Martin, L.J., Z. Liu, J. Pipino, et al. 2008. Molecular regulation of DNA damage-induced apoptosis in
neurons of cerebral cortex. Cereb. Cortex. Epub ahead
of print.
24. Nouspikel, T. & P.C. Hanawalt. 2000. Terminally differentiated human neurons repair transcribed genes
but display attenuated global DNA repair and modulation of repair gene expression. Mol. Cell Biol. 20:
1562–1570.
25. Nouspikel, T. & P.C. Hanawalt. 2003. When parsimony backfires: neglecting DNA repair may doom
neurons in Alzheimer’s disease. Bioessays 25: 168–
173.
26. Kruman, I.I. 2004. Why do neurons enter the cell
cycle? Cell Cycle 3: 769–773.
27. Mellon, P.L. et al. 1990. Immortalization of hypothalamic GnRH neurons by genetically targeted tumorigenesis. Neuron 5: 1–10.
28. Eves, E.M. et al. 1994. Conditional immortalization
of neuronal cells from postmitotic cultures and adult
CNS. Brain Res. 656: 396–404.
29. Kruman, I.I. et al. 2004. Cell cycle activation linked to
neuronal cell death initiated by DNA damage. Neuron
41: 549–561.
30. Kim, D. et al. 2007. SIRT1 deacetylase protects
against neurodegeneration in models for Alzheimer’s
disease and amyotrophic lateral sclerosis. Embo J. 26:
3169–3179.
31. Laine, H. et al. 2007. p19(Ink4d) and p21(Cip1) collaborate to maintain the postmitotic state of auditory
hair cells, their codeletion leading to DNA damage
and p53-mediated apoptosis. J. Neurosci. 27: 1434–
1444.
32. Klein, J.A. et al. 2002. The harlequin mouse mutation
downregulates apoptosis-inducing factor. Nature 419:
367–374.
33. Patrick, G.N. et al. 1999. Conversion of p35 to p25
deregulates Cdk5 activity and promotes neurodegeneration. Nature 402: 615–622.
34. Wang, J., S. Liu, Y. Fu, et al. 2003. Cdk5 activation induces hippocampal CA1 cell death by directly
phosphorylating NMDA receptors. Nat. Neurosci. 6:
1039–1047.
35. Cruz, J.C., H.C. Tseng, J.A. Goldman, et al. 2003.
Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40: 471–483.
36. Cruz, J.C. et al. 2006. p25/cyclin-dependent kinase 5
induces production and intraneuronal accumulation
of amyloid beta in vivo. J. Neurosci. 26: 10536–10541.
37. Fischer, A., F. Sananbenesi, P.T. Pang, et al. 2005.
Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampusdependent memory. Neuron 48: 825–838.
38. Kim, D. et al. 2008. Deregulation of HDAC1 by
p25/Cdk5 in neurotoxicity. Neuron 60: 803–817.
39. Branzei, D. & M. Foiani. 2005. The DNA damage
response during DNA replication. Curr. Opin. Cell Biol.
17: 568–575.
40. Gabellini, D., M.R. Green & R. Tupler. 2004. When
enough is enough: genetic diseases associated with
transcriptional derepression. Curr. Opin. Genet. Dev.
14: 301–307.
41. Saha, R.N. & K. Pahan. 2006. HATs and HDACs in
neurodegeneration: a tale of disconcerted acetylation
homeostasis. Cell Death Differ. 13: 539–550.
42. Morales, V. et al. 2001. Chromatin structure and dynamics: functional implications. Biochimie 83: 1029–
1039.
43. Blais, A. & B.D. Dynlacht. 2007. E2F-associated
chromatin modifiers and cell cycle control. Curr. Opin.
Cell Biol. 19: 658–662.
44. Folle, G.A., W. Martinez-Lopez, E. Boccardo & G.
Obe. 1998. Localization of chromosome breakpoints:
implication of the chromatin structure and nuclear
architecture. Mutat. Res. 404: 17–26.
45. Cerna, D., K. Camphausen & P.J. Tofilon. 2006. Histone deacetylation as a target for radiosensitization.
Curr. Top. Dev. Biol. 73: 173–204.
46. Smerdon, M.J. & A. Conconi. 1999. Modulation of
DNA damage and DNA repair in chromatin. Prog.
Nucleic Acid Res. Mol. Biol. 62: 227–255.