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Chromatin Modifications Associated with DNA Double-strand Breaks Repair as Potential Targets for Neurological Diseases

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Neurotherapeutics

Abstract

The integrity of the genome is continuously challenged by both endogenous and exogenous DNA damaging agents. Neurons, due to their post-mitotic state, high metabolism, and longevity are particularly prone to the accumulation of DNA lesions. Indeed, DNA damage has been suggested as a major contributor to both age-associated neurodegenerative diseases and acute neurological injury. The DNA damage response is a key factor in maintaining genome integrity. It relies on highly dynamic posttranslational modifications of the chromatin and DNA repair proteins to allow signaling, access, and repair of the lesion. Drugs that modulate the activity of the enzymes responsible for these modifications have emerged as attractive therapeutic compounds to treat neurodegeneration. In this review, we discuss the role of DNA double-strand breaks and abnormal chromatin modification patterns in a range of neurodegenerative conditions, and the chromatin modifiers that might ameliorate them. Finally, we suggest that understanding the epigenetic modifications specific to neuronal DNA repair is crucial for the development of efficient neurotherapeutic strategies.

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References

  1. Dudley DD, Chaudhuri J, Bassing CH, Alt FW. Mechanism and control of V(D)J recombination versus class switch recombination: similarities and differences. Adv Immunol 2005;86:43–112.

    PubMed  CAS  Google Scholar 

  2. Keeney S, Neale MJ. Initiation of meiotic recombination by formation of DNA double-strand breaks: mechanism and regulation. Biochem Soc Trans 2006;34:523–525.

    PubMed  CAS  Google Scholar 

  3. Aziz K, Nowsheen S, Pantelias G, Iliakis G, Gorgoulis VG, Georgakilas AG. Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy. Pharmacol Therapeut 2012;133:334–350.

    CAS  Google Scholar 

  4. Kenyon J, Gerson SL. The role of DNA damage repair in aging of adult stem cells. Nucleic Acids Res 2007;35:7557–7565.

    PubMed  CAS  Google Scholar 

  5. Nouspikel T, Hanawalt PC. Terminally differentiated human neurons repair transcribed genes but display attenuated global DNA repair and modulation of repair gene expression. Mol Cell Biol 2000;20:1562–1570.

    PubMed  CAS  Google Scholar 

  6. Nouspikel T. DNA repair in differentiated cells: some new answers to old questions. Neuroscience. 2007;145:1213–1221.

    PubMed  CAS  Google Scholar 

  7. Luijsterburg MS, van Attikum H. Chromatin and the DNA damage response: the cancer connection. Molec Oncol. 2011;5:349–367.

    CAS  Google Scholar 

  8. Miller KM, Jackson SP. Histone marks: repairing DNA breaks within the context of chromatin. Biochem Soc Trans 2012;40:370–6.

    PubMed  CAS  Google Scholar 

  9. Wu J, Grunstein M. 25 years after the nucleosome model: chromatin modifications. Trends Biochem Sci. 2000;25:619–23.

    PubMed  CAS  Google Scholar 

  10. Wysocka J, Swigut T, Milne TA, Dou Y, Zhang X, Burlingame AL et al. WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell 2005;121:859–872.

    PubMed  CAS  Google Scholar 

  11. Zeng L, Zhou MM. Bromodomain: an acetyl-lysine binding domain. FEBS Lett. 2002;513:124–128.

    PubMed  CAS  Google Scholar 

  12. Jenuwein T, Allis CD. Translating the histone code. Science 2001;293(5532):1074–1080.

    PubMed  CAS  Google Scholar 

  13. Falck J, Coates J, Jackson SP. Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Nature 2005;434(7033):605–611.

    PubMed  CAS  Google Scholar 

  14. Lee JH, Paull TT. Activation and regulation of ATM kinase activity in response to DNA double-strand breaks. Oncogene 2007;26(56):7741–7748.

    PubMed  CAS  Google Scholar 

  15. Kinner A, Wu W, Staudt C, Iliakis G. Gamma-H2AX in recognition and signaling of DNA double-strand breaks in the context of chromatin. Nucleic Acids Res 2008;36(17):5678–5694.

    PubMed  CAS  Google Scholar 

  16. Yun MH, Hiom K. Understanding the functions of BRCA1 in the DNA-damage response. Biochem Soc Trans 2009;37(3):597–604.

    PubMed  CAS  Google Scholar 

  17. Lee JH, Goodarzi AA, Jeggo PA, Paull TT. 53BP1 promotes ATM activity through direct interactions with the MRN complex. EMBO J 2010;29(3):574–585.

    PubMed  CAS  Google Scholar 

  18. Goldberg M, Stucki M, Falck J, D'Amours D, Rahman D, Pappin D et al. MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature 2003;421(6926):952–956.

    PubMed  CAS  Google Scholar 

  19. Tang J, Cho NW, Cui G, Manion EM, Shanbhag NM, Botuyan MV et al. Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nature Struct Molec Biol 2013;20(3):317–325.

    CAS  Google Scholar 

  20. Lieber MR, Ma Y, Pannicke U, Schwarz K. Mechanism and regulation of human non-homologous DNA end-joining. Nature Rev Molec Cell Biol 2003;4(9):712–720.

    CAS  Google Scholar 

  21. Wyman C, Ristic D, Kanaar R. Homologous recombination-mediated double-strand break repair. DNA Repair 2004;3(8–9):827–833.

    PubMed  CAS  Google Scholar 

  22. Doherty AJ, Jackson SP. DNA repair: how Ku makes ends meet. Current Biol: CB 2001;11(22):R920–924.

    CAS  Google Scholar 

  23. Daley JM, Laan RL, Suresh A, Wilson TE. DNA joint dependence of pol X family polymerase action in nonhomologous end joining. J Biological Chem. 2005;280(32):29030–7.

    CAS  Google Scholar 

  24. Wilson TE, Grawunder U, Lieber MR. Yeast DNA ligase IV mediates non-homologous DNA end joining. Nature 1997;388(6641):495–458.

    PubMed  CAS  Google Scholar 

  25. Sykora P, Wilson DM, 3rd, Bohr VA. Base excision repair in the mammalian brain: Implication for age related neurodegeneration. Mech Ageing Devel 2013. doi:10.1016/j.mad.2013.04.005

    Google Scholar 

  26. Canugovi C, Misiak M, Ferrarelli LK, Croteau DL, Bohr VA. The role of DNA repair in brain related disease pathology. DNA Repair 2013;12(8):578–587.

    PubMed  CAS  Google Scholar 

  27. Yamamori T, DeRicco J, Naqvi A, Hoffman TA, Mattagajasingh I, Kasuno K et al. SIRT1 deacetylates APE1 and regulates cellular base excision repair. Nucleic Acids Res 2010;38(3):832–845.

    PubMed  CAS  Google Scholar 

  28. Fan W, Luo J. SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Molecular Cell. 2010;39(2):247–258.

    PubMed  CAS  Google Scholar 

  29. Ikura T, Tashiro S, Kakino A, Shima H, Jacob N, Amunugama R et al. DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Molec Cell Biol 2007;27(20):7028–7040.

    PubMed  CAS  Google Scholar 

  30. Murr R, Loizou JI, Yang YG, Cuenin C, Li H, Wang ZQ et al. Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nature Cell Biol 2006;8(1):91–99.

    PubMed  CAS  Google Scholar 

  31. Li X, Corsa CA, Pan PW, Wu L, Ferguson D, Yu X et al. MOF and H4 K16 acetylation play important roles in DNA damage repair by modulating recruitment of DNA damage repair protein Mdc1. Molec Cell Biol 2010;30(22):5335–5347.

    PubMed  CAS  Google Scholar 

  32. Sharma GG, So S, Gupta A, Kumar R, Cayrou C, Avvakumov N et al. MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. Molec Cell Biol 2010;30(14):3582–3595.

    PubMed  CAS  Google Scholar 

  33. Choudhary C, Kumar C, Gnad F, Nielsen ML, Rehman M, Walther TC et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science 2009;325(5942):834–840.

    PubMed  CAS  Google Scholar 

  34. Sun Y, Jiang X, Chen S, Fernandes N, Price BD. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(37):13182–13187.

    PubMed  CAS  Google Scholar 

  35. Wang J, Chen J. SIRT1 regulates autoacetylation and histone acetyltransferase activity of TIP60. J Biol Chem. 2010;285(15):11458–11464.

    PubMed  CAS  Google Scholar 

  36. Chen CS, Wang YC, Yang HC, Huang PH, Kulp SK, Yang CC et al. Histone deacetylase inhibitors sensitize prostate cancer cells to agents that produce DNA double-strand breaks by targeting Ku70 acetylation. Cancer Res 2007;67(11):5318–5327.

    PubMed  CAS  Google Scholar 

  37. Kerr E, Holohan C, McLaughlin KM, Majkut J, Dolan S, Redmond K et al. Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis. Cell Death Differ 2012;19(8):1317–1327.

    PubMed  CAS  Google Scholar 

  38. Subramanian C, Jarzembowski JA, Opipari AW, Jr., Castle VP, Kwok RP. HDAC6 deacetylates Ku70 and regulates Ku70-Bax binding in neuroblastoma. Neoplasia 2011;13(8):726–734.

    PubMed  CAS  Google Scholar 

  39. Kachhap SK, Rosmus N, Collis SJ, Kortenhorst MS, Wissing MD, Hedayati M et al. Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PloS One 5(6):e11208.

  40. Boutillier AL, Trinh E, Loeffler JP. Selective E2F-dependent gene transcription is controlled by histone deacetylase activity during neuronal apoptosis. J Neurochem. 2003;84(4):814–828.

    PubMed  CAS  Google Scholar 

  41. Kachhap SK, Rosmus N, Collis SJ, Kortenhorst MS, Wissing MD, Hedayati M et al. Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PloS One 2010;5(6):e11208.

    PubMed  Google Scholar 

  42. Jang ER, Choi JD, Park MA, Jeong G, Cho H, Lee JS. ATM modulates transcription in response to histone deacetylase inhibition as part of its DNA damage response. Exp Molec Med 2010;42(3):195–204.

    CAS  Google Scholar 

  43. Lee JS. Functional link between DNA damage responses and transcriptional regulation by ATM in response to a histone deacetylase inhibitor TSA. Cancer Res Treat 2007;39(3):116–124.

    PubMed  Google Scholar 

  44. Adimoolam S, Sirisawad M, Chen J, Thiemann P, Ford JM, Buggy JJ. HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proceedings of the National Academy of Sciences of the United States of America 2007;104(49):19482–19487.

    PubMed  CAS  Google Scholar 

  45. Lopez G, Liu J, Ren W, Wei W, Wang S, Lahat G et al. Combining PCI-24781, a novel histone deacetylase inhibitor, with chemotherapy for the treatment of soft tissue sarcoma. Clin Cancer Res 2009;15(10):3472–3483.

    PubMed  CAS  Google Scholar 

  46. Ozaki T, Okoshi R, Sang M, Kubo N, Nakagawara A. Acetylation status of E2F-1 has an important role in the regulation of E2F-1-mediated transactivation of tumor suppressor p73. Biochem Biophys Res Commun 2009;386(1):207–211.

    PubMed  CAS  Google Scholar 

  47. Pediconi N, Ianari A, Costanzo A, Belloni L, Gallo R, Cimino L et al. Differential regulation of E2F1 apoptotic target genes in response to DNA damage. Nature Cell Biol 2003;5(6):552–558.

    PubMed  CAS  Google Scholar 

  48. Brochier C, Dennis G, Rivieccio MA, McLaughlin K, Coppola G, Ratan RR et al. Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons. J Neurosci 2013;33(20):8621–8532.

    PubMed  CAS  Google Scholar 

  49. Jazayeri A, McAinsh AD, Jackson SP. Saccharomyces cerevisiae Sin3p facilitates DNA double-strand break repair. Proceedings of the National Academy of Sciences of the United States of America 2004;101(6):1644–1649.

    PubMed  CAS  Google Scholar 

  50. Miller KM, Tjeertes JV, Coates J, Legube G, Polo SE, Britton S et al. Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nature Structural Molec Biol 2010;17(9):1144–1151.

    CAS  Google Scholar 

  51. Bhaskara S, Chyla BJ, Amann JM, Knutson SK, Cortez D, Sun ZW et al. Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Molecular Cell 2008;30(1):61–72.

    PubMed  CAS  Google Scholar 

  52. Bhaskara S, Knutson SK, Jiang G, Chandrasekharan MB, Wilson AJ, Zheng S et al. Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 2010;18(5):436–447.

    PubMed  CAS  Google Scholar 

  53. Kao GD, McKenna WG, Guenther MG, Muschel RJ, Lazar MA, Yen TJ. Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response. J Cell Biol 2003;160(7):1017–1027.

    PubMed  CAS  Google Scholar 

  54. Basile V, Mantovani R, Imbriano C. DNA damage promotes histone deacetylase 4 nuclear localization and repression of G2/M promoters, via p53 C-terminal lysines. J Biol Chem 2006;281(4):2347–2357.

    PubMed  CAS  Google Scholar 

  55. Kotian S, Liyanarachchi S, Zelent A, Parvin JD. Histone deacetylases 9 and 10 are required for homologous recombination. J Biol Chem 2011;286(10):7722–7726.

    PubMed  CAS  Google Scholar 

  56. Stucki M. Histone H2A.X Tyr142 phosphorylation: a novel sWItCH for apoptosis? DNA Repair 2009;8(7):873–876.

    PubMed  CAS  Google Scholar 

  57. Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 2009;458(7238):591–596.

    PubMed  CAS  Google Scholar 

  58. Pattaroni C, Jacob C. Histone methylation in the nervous system: functions and dysfunctions. Molec Neurobiol 2013;47(2):740–756.

    CAS  Google Scholar 

  59. Kruhlak MJ, Celeste A, Nussenzweig A. Spatio-temporal dynamics of chromatin containing DNA breaks. Cell Cycle. 2006;5(17):1910–1912.

    PubMed  CAS  Google Scholar 

  60. Ziv Y, Bielopolski D, Galanty Y, Lukas C, Taya Y, Schultz DC et al. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nature Cell Biol 2006;8(8):870–876.

    PubMed  CAS  Google Scholar 

  61. O'Hagan HM, Mohammad HP, Baylin SB. Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genetics 2008;4(8):e1000155.

    PubMed  Google Scholar 

  62. Seiler DM, Rouquette J, Schmid VJ, Strickfaden H, Ottmann C, Drexler GA et al. Double-strand break-induced transcriptional silencing is associated with loss of tri-methylation at H3K4. Chromosome Res 2011;19(7):883–899.

    PubMed  CAS  Google Scholar 

  63. Sanders SL, Portoso M, Mata J, Bahler J, Allshire RC, Kouzarides T. Methylation of histone H4 lysine 20 controls recruitment of Crb2 to sites of DNA damage. Cell 2004;119(5):603–614.

    PubMed  CAS  Google Scholar 

  64. Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 2006;127(7):1361–1373.

    PubMed  CAS  Google Scholar 

  65. Messner S, Altmeyer M, Zhao H, Pozivil A, Roschitzki B, Gehrig P et al. PARP1 ADP-ribosylates lysine residues of the core histone tails. Nucleic Acids Res 2010;38(19):6350–6362.

    PubMed  CAS  Google Scholar 

  66. Monks TJ, Xie R, Tikoo K, Lau SS. Ros-induced histone modifications and their role in cell survival and cell death. Drug Metab Rev 2006;38(4):755–767.

    PubMed  CAS  Google Scholar 

  67. Schreiber V, Dantzer F, Ame JC, de Murcia G. Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Bio 2006;7(7):517–528.

    CAS  Google Scholar 

  68. Chou DM, Adamson B, Dephoure NE, Tan X, Nottke AC, Hurov KE et al. A chromatin localization screen reveals poly (ADP ribose)-regulated recruitment of the repressive polycomb and NuRD complexes to sites of DNA damage. Proceedings of the National Academy of Sciences of the United States of America 2010;107(43):18475–18480.

    PubMed  CAS  Google Scholar 

  69. Ahel D, Horejsi Z, Wiechens N, Polo SE, Garcia-Wilson E, Ahel I et al. Poly(ADP-ribose)-dependent regulation of DNA repair by the chromatin remodeling enzyme ALC1. Science 2009;325(5945):1240–1243.

    PubMed  CAS  Google Scholar 

  70. Hottiger MO, Boothby M, Koch-Nolte F, Luscher B, Martin NM, Plummer R et al. Progress in the function and regulation of ADP-Ribosylation. Science Signal 2011;4(174):mr5.

    Google Scholar 

  71. Timinszky G, Till S, Hassa PO, Hothorn M, Kustatscher G, Nijmeijer B et al. A macrodomain-containing histone rearranges chromatin upon sensing PARP1 activation. Nat Struct Molec Biol 2009;16(9):923–929.

    CAS  Google Scholar 

  72. Wang M, Wu W, Wu W, Rosidi B, Zhang L, Wang H et al. PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways. Nucleic Acids Res 2006;34(21):6170–6182.

    PubMed  CAS  Google Scholar 

  73. Lu T, Pan Y, Kao SY, Li C, Kohane I, Chan J et al. Gene regulation and DNA damage in the ageing human brain. Nature 2004;429(6994):883–891.

    PubMed  CAS  Google Scholar 

  74. Barzilai A, Biton S, Shiloh Y. The role of the DNA damage response in neuronal development, organization and maintenance. DNA Repair 2008;7(7):1010–1027.

    PubMed  CAS  Google Scholar 

  75. Peleg S, Sananbenesi F, Zovoilis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC et al. Altered histone acetylation is associated with age-dependent memory impairment in mice. Science 2010;328(5979):753–756.

    PubMed  CAS  Google Scholar 

  76. Krishnan V, Chow MZ, Wang Z, Zhang L, Liu B, Liu X et al. Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 2011;108(30):12325–12330.

    PubMed  CAS  Google Scholar 

  77. Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP et al. Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 2011;479(7373):365–371.

    PubMed  CAS  Google Scholar 

  78. Cheung I, Shulha HP, Jiang Y, Matevossian A, Wang J, Weng Z et al. Developmental regulation and individual differences of neuronal H3K4me3 epigenomes in the prefrontal cortex. Proceedings of the National Academy of Sciences of the United States of America 2010;107(19):8824–8829.

    PubMed  CAS  Google Scholar 

  79. Han Y, Han D, Yan Z, Boyd-Kirkup JD, Green CD, Khaitovich P et al. Stress-associated H3K4 methylation accumulates during postnatal development and aging of rhesus macaque brain. Aging Cell 2012;11(6):1055–1064.

    PubMed  CAS  Google Scholar 

  80. Jensen LR, Amende M, Gurok U, Moser B, Gimmel V, Tzschach A et al. Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. Am J Hum Genet 2005;76(2):227–236.

    PubMed  CAS  Google Scholar 

  81. Wang CM, Tsai SN, Yew TW, Kwan YW, Ngai SM. Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8. Biogerontology 2010;11(1):87–102.

    PubMed  CAS  Google Scholar 

  82. Ji X, Luo Y, Ling F, Stetler RA, Lan J, Cao G et al. Mild hypothermia diminishes oxidative DNA damage and pro-death signaling events after cerebral ischemia: a mechanism for neuroprotection. Front Biosci 2007;12:1737–1747.

    PubMed  CAS  Google Scholar 

  83. Jin K, Chen J, Nagayama T, Chen M, Sinclair J, Graham SH et al. In situ detection of neuronal DNA strand breaks using the Klenow fragment of DNA polymerase I reveals different mechanisms of neuron death after global cerebral ischemia. J Neurochem 1999;72(3):1204–1214.

    PubMed  CAS  Google Scholar 

  84. Nagayama T, Lan J, Henshall DC, Chen D, O'Horo C, Simon RP et al. Induction of oxidative DNA damage in the peri-infarct region after permanent focal cerebral ischemia. J Neurochem 2000;75(4):1716–1728.

    PubMed  CAS  Google Scholar 

  85. Kotipatruni RR, Dasari VR, Veeravalli KK, Dinh DH, Fassett D, Rao JS. p53- and Bax-mediated apoptosis in injured rat spinal cord. Neurochem Res 2011;36(11):2063–2074.

    PubMed  CAS  Google Scholar 

  86. Martin LJ, Liu Z. Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and Bax-dependent. J Neurobiol 2002;50(3):181–197.

    PubMed  CAS  Google Scholar 

  87. Mullaart E, Boerrigter ME, Ravid R, Swaab DF, Vijg J. Increased levels of DNA breaks in cerebral cortex of Alzheimer's disease patients. Neurobiol Aging 1990;11(3):169–173.

    PubMed  CAS  Google Scholar 

  88. Lyras L, Cairns NJ, Jenner A, Jenner P, Halliwell B. An assessment of oxidative damage to proteins, lipids, and DNA in brain from patients with Alzheimer's disease. J Neurochem 1997;68(5):2061–2069.

    PubMed  CAS  Google Scholar 

  89. Shackelford DA. DNA end joining activity is reduced in Alzheimer's disease. Neurobiol Aging 2006;27(4):596–605.

    PubMed  CAS  Google Scholar 

  90. Minopoli G, Stante M, Napolitano F, Telese F, Aloia L, De Felice M et al. Essential roles for Fe65, Alzheimer amyloid precursor-binding protein, in the cellular response to DNA damage. J Biol Chem 2007;282(2):831–835.

    PubMed  CAS  Google Scholar 

  91. Illuzzi J, Yerkes S, Parekh-Olmedo H, Kmiec EB. DNA breakage and induction of DNA damage response proteins precede the appearance of visible mutant huntingtin aggregates. J Neurosci Res 2009;87(3):733–747.

    PubMed  CAS  Google Scholar 

  92. Jeon GS, Kim KY, Hwang YJ, Jung MK, An S, Ouchi M et al. Deregulation of BRCA1 leads to impaired spatiotemporal dynamics of gamma-H2AX and DNA damage responses in Huntington's disease. Molec Neurobiol 2012;45(3):550–563.

    CAS  Google Scholar 

  93. Lotharius J, Brundin P. Pathogenesis of Parkinson's disease: dopamine, vesicles and alpha-synuclein. Nat Rev Neurosci 2002;3(12):932–942.

    PubMed  CAS  Google Scholar 

  94. Hegde ML, Gupta VB, Anitha M, Harikrishna T, Shankar SK, Muthane U et al. Studies on genomic DNA topology and stability in brain regions of Parkinson's disease. Arch Biochem Biophys 2006;449(1–2):143–156.

    PubMed  CAS  Google Scholar 

  95. Eilam R, Peter Y, Elson A, Rotman G, Shiloh Y, Groner Y et al. Selective loss of dopaminergic nigro-striatal neurons in brains of Atm-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 1998;95(21):12653–12656.

    PubMed  CAS  Google Scholar 

  96. Shackelford RE, Fu Y, Manuszak RP, Brooks TC, Sequeira AP, Wang S et al. Iron chelators reduce chromosomal breaks in ataxia-telangiectasia cells. DNA Repair 2006;5(11):1327–1336.

    PubMed  CAS  Google Scholar 

  97. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362(6415):59–62.

    PubMed  CAS  Google Scholar 

  98. Martin LJ, Chen K, Liu Z. Adult motor neuron apoptosis is mediated by nitric oxide and Fas death receptor linked by DNA damage and p53 activation. J Neurosci 2005;25(27):6449–6459.

    PubMed  CAS  Google Scholar 

  99. Martin LJ, Liu Z, Chen K, Price AC, Pan Y, Swaby JA et al. Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death. J Comp Neurol 2007;500(1):20–46.

    PubMed  CAS  Google Scholar 

  100. Shaikh AY, Martin LJ. DNA base-excision repair enzyme apurinic/apyrimidinic endonuclease/redox factor-1 is increased and competent in the brain and spinal cord of individuals with amyotrophic lateral sclerosis. Neuromolec Med 2002;2(1):47–60.

    CAS  Google Scholar 

  101. Rouaux C, Loeffler JP, Boutillier AL. Targeting CREB-binding protein (CBP) loss of function as a therapeutic strategy in neurological disorders. Biochem Pharmacol 2004;68(6):1157–1164.

    PubMed  CAS  Google Scholar 

  102. Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH. Recovery of learning and memory is associated with chromatin remodelling. Nature 2007;447(7141):178–182.

    PubMed  CAS  Google Scholar 

  103. Rivieccio MA, Brochier C, Willis DE, Walker BA, D'Annibale MA, McLaughlin K et al. HDAC6 is a target for protection and regeneration following injury in the nervous system. Proceedings of the National Academy of Sciences of the United States of America 2009;106(46):19599–19604.

    PubMed  CAS  Google Scholar 

  104. Kazantsev AG, Thompson LM. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Disc 2008;7(10):854–868.

    CAS  Google Scholar 

  105. Langley B, Brochier C, Rivieccio MA. Targeting histone deacetylases as a multifaceted approach to treat the diverse outcomes of stroke. Stroke 2009;40(8):2899–2905.

    PubMed  CAS  Google Scholar 

  106. Kim D, Frank CL, Dobbin MM, Tsunemoto RK, Tu W, Peng PL et al. Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron 2008;60(5):803–817.

    PubMed  CAS  Google Scholar 

  107. Graff J, Rei D, Guan JS, Wang WY, Seo J, Hennig KM et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 2012;483(7388):222–226.

    PubMed  Google Scholar 

  108. Bardai FH, D'Mello SR. Selective toxicity by HDAC3 in neurons: regulation by Akt and GSK3beta. J Neurosci 2011;31(5):1746–1751.

    PubMed  CAS  Google Scholar 

  109. Munshi A, Kurland JF, Nishikawa T, Tanaka T, Hobbs ML, Tucker SL et al. Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res 2005;11(13):4912–4922.

    PubMed  CAS  Google Scholar 

  110. Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell Res 2008;18(1):134–147.

    PubMed  CAS  Google Scholar 

  111. Yaneva M, Li H, Marple T, Hasty P. Non-homologous end joining, but not homologous recombination, enables survival for cells exposed to a histone deacetylase inhibitor. Nucleic Acids Res 2005;33(16):5320–5330.

    PubMed  CAS  Google Scholar 

  112. Wang Y, Dawson VL, Dawson TM. Poly(ADP-ribose) signals to mitochondrial AIF: a key event in parthanatos. Exp Neurol 2009;218(2):193–202.

    PubMed  CAS  Google Scholar 

  113. Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA. Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J Cerebr Blood F Met 1997;17(11):1143–1151.

    CAS  Google Scholar 

  114. Jagtap P, Szabo C. Poly(ADP-ribose) polymerase and the therapeutic effects of its inhibitors. Nat Rev Drug Discov 2005;4(5):421–440.

    PubMed  CAS  Google Scholar 

  115. Copeland RA, Olhava EJ, Scott MP. Targeting epigenetic enzymes for drug discovery. Curr Opin Chem Biol 2010;14(4):505–610.

    PubMed  CAS  Google Scholar 

  116. Kerimoglu C, Agis-Balboa RC, Kranz A, Stilling R, Bahari-Javan S, Benito-Garagorri E et al. Histone-methyltransferase MLL2 (KMT2B) is required for memory formation in mice. J Neurosci 2013;33(8):3452–3464.

    PubMed  CAS  Google Scholar 

  117. Balemans MC, Kasri NN, Kopanitsa MV, Afinowi NO, Ramakers G, Peters TA et al. Hippocampal dysfunction in the Euchromatin histone methyltransferase 1 heterozygous knockout mouse model for Kleefstra syndrome. Hum Mol Genet 2013;22(5):852–866.

    PubMed  CAS  Google Scholar 

  118. Gupta-Agarwal S, Franklin AV, Deramus T, Wheelock M, Davis RL, McMahon LL et al. G9a/GLP histone lysine dimethyltransferase complex activity in the hippocampus and the entorhinal cortex is required for gene activation and silencing during memory consolidation. J Neurosci 2012;32(16):5440–5453.

    PubMed  CAS  Google Scholar 

  119. Gupta S, Kim SY, Artis S, Molfese DL, Schumacher A, Sweatt JD et al. Histone methylation regulates memory formation. J Neurosci 2010;30(10):3589–3599.

    PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the National Institutes of Health (NS071056), the New York State Spinal Cord Injury Research Program (CO19772), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, and the Burke Medical Research Foundation.

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  1. The Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY, 10605, USA

    Camille Brochier & Brett Langley

  2. Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY, 10065, USA

    Camille Brochier & Brett Langley

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  1. Camille Brochier
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  2. Brett Langley
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Correspondence to Camille Brochier.

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Brochier, C., Langley, B. Chromatin Modifications Associated with DNA Double-strand Breaks Repair as Potential Targets for Neurological Diseases. Neurotherapeutics 10, 817–830 (2013). https://doi.org/10.1007/s13311-013-0210-9

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