Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer

Nature Reviews Cancer

Volumn 12, Issue 10, 2012, Pages 709-720

  Sulli, Gabriele ^a,b   Di Micco, Raffaella ^a,c   Di Fagagna, Fabrizio D'Adda ^a,d  

^a FIRC INSTITUTE OF MOLECULAR ONCOLOGY   (Italy)

^b SALK INSTITUTE FOR BIOLOGICAL STUDIES   (United States)

^c NEW YORK UNIVERSITY SCHOOL OF MEDICINE   (United States)

^d CNR   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CARCINOGENESIS; CELL AGING; CHROMATIN; CHROMATIN ASSEMBLY AND DISASSEMBLY; DNA DAMAGE; GENOMIC INSTABILITY; ONCOGENE; PRIORITY JOURNAL; REVIEW;

ANIMALS; CELL AGING; CHROMATIN; DNA; DNA DAMAGE; DNA REPAIR; HISTONES; HUMANS; NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84866741381     PISSN: 1474175X     EISSN: 14741768     Source Type: Journal    
DOI: 10.1038/nrc3344     Document Type: Review

References (148)

1. Kornberg, R. D. Chromatin structure: a repeating unit of histones and DNA. Science 184, 868-871 (1974).
2. Dillon, N. Heterochromatin structure and function. Biol. Cell 96, 631-637 (2004).
3. d'Adda di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nature Rev. Cancer 8, 512-522 (2008).
4. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352-1355 (2008).
5. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638-642 (2006).
6. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633-637 (2006).
7. Lopez-Contreras, A. J. & Fernandez-Capetillo, O. The ATR barrier to replication-born DNA damage. DNA Repair 9, 1249-1255 (2010).
8. Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nature Cell Biol. 14, 355-365 (2012).
9. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585-621 (1961).
10. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593-602 (1997).
11. Evan, G. I. & d'Adda di Fagagna, F. Cellular senescence: hot or what? Curr. Opin. Genet. Dev. 19, 25-31 (2009).
12. Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071-1078 (2009).
13. Collado, M. & Serrano, M. The power and the promise of oncogene-induced senescence markers. Nature Rev. Cancer 6, 472-476 (2006).
14. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864-870 (2005).
15. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907-913 (2005).
16. Lee, A. C. et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274, 7936-7940 (1999).
17. Ogrunc, M. & di Fagagna, F. Never-ageing cellular senescence. Eur. J. Cancer 47, 1616-1622 (2011).
18. Elia, M. C. & Bradley, M. O. Influence of chromatin structure on the induction of DNA double strand breaks by ionizing radiation. Cancer Res. 52, 1580-1586 (1992).
19. Costes, S. V. et al. Image-based modeling reveals dynamic redistribution of DNA damage into nuclear sub-domains. PLoS Comput. Biol. 3, e155 (2007).
20. Cowell, I. G. et al. γH2AX foci form preferentially in euchromatin after ionising-radiation. PLoS ONE 2, e1057 (2007).
21. Di Micco, R. et al. Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer. Nature Cell Biol. 13, 292-302 (2011).
22. Kim, J. A., Kruhlak, M., Dotiwala, F., Nussenzweig, A. & Haber, J. E. Heterochromatin is refractory to γ-H2AX modification in yeast and mammals. J. Cell Biol. 178, 209-218 (2007).
23. Murga, M. et al. Global chromatin compaction limits the strength of the DNA damage response. J. Cell Biol. 178, 1101-1108 (2007).
24. Iacovoni, J. S. et al. High-resolution profiling of γH2AX around DNA double strand breaks in the mammalian genome. EMBO J. 29, 1446-1457 (2010).
25. Goodarzi, A. A. et al. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol. Cell 31, 167-177 (2008).
26. Goodarzi, A. A., Kurka, T. & Jeggo, P. A. KAP-1 phosphorylation regulates CHD3 nucleosome remodeling during the DNA double-strand break response. Nature Struct. Mol. Biol. 18, 831-839 (2011).
27. Denslow, S. A. & Wade, P. A. The human Mi-2/NuRD complex and gene regulation. Oncogene 26, 5433-5438 (2007).
28. Yokoe, T. et al. KAP1 is associated with peritoneal carcinomatosis in gastric cancer. Ann. Surg. Oncol. 17, 821-828 (2010).
29. Ho, J. et al. Novel breast cancer metastasis-associated proteins. J. Proteome Res. 8, 583-594 (2009).
30. Chiolo, I. et al. Double-strand breaks in heterochromatin move outside of a dynamic HP1a domain to complete recombinational repair. Cell 144, 732-744 (2011).
31. Kruhlak, M. J. et al. Changes in chromatin structure and mobility in living cells at sites of DNA double-strand breaks. J. Cell Biol. 172, 823-834 (2006).
32. Soutoglou, E. et al. Positional stability of single double-strand breaks in mammalian cells. Nature Cell Biol. 9, 675-682 (2007).
33. Pentimalli, F. et al. HMGA1 protein is a novel target of the ATM kinase. Eur. J. Cancer 44, 2668-2679 (2008).
34. Palmieri, D. et al. HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents. Oncogene 30, 3024-3035 (2011).
35. Fedele, M. & Fusco, A. HMGA and cancer. Biochim. Biophys. Acta 1799, 48-54 (2010).
36. van Attikum, H., Fritsch, O., Hohn, B. & Gasser, S. M. Recruitment of the INO80 complex by H2A phosphorylation links ATP-dependent chromatin remodeling with DNA double-strand break repair. Cell 11 9, 777-788 (2004).
37. Morrison, A. J. et al. INO80 and γ-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair. Cell 11 9, 767-775 (2004).
38. Wu, S. et al. A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair. Nature Struct. Mol. Biol. 14, 1165-1172 (2007).
39. Gospodinov, A. et al. Mammalian Ino80 mediates double-strand break repair through its role in DNA end strand resection. Mol. Cell. Biol. 31, 4735-4745 (2011).
40. Kashiwaba, S. et al. The mammalian INO80 complex is recruited to DNA damage sites in an ARP8 dependent manner. Biochem. Biophys. Res. Commun. 402, 619-625 (2010).
41. Papamichos-Chronakis, M. & Peterson, C. L. The Ino80 chromatin-remodeling enzyme regulates replisome function and stability. Nature Struct. Mol. Biol. 15, 338-345 (2008).
42. Papamichos-Chronakis, M., Watanabe, S., Rando, O. J. & Peterson, C. L. Global regulation of H2A.Z localization by the INO80 chromatin-remodeling enzyme is essential for genome integrity. Cell 144, 200-213 (2011).
43. Dominguez-Sola, D. et al. Non-transcriptional control of DNA replication by c-Myc. Nature 448, 445-451 (2007).
44. Park, J. H. et al. Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting γ-H2AX induction. EMBO J. 25, 3986-3997 (2006).
45. Klochendler-Yeivin, A., Picarsky, E. & Yaniv, M. Increased DNA damage sensitivity and apoptosis in cells lacking the Snf5/Ini1 subunit of the SWI/SNF chromatin remodeling complex. Mol. Cell. Biol. 26, 2661-2674 (2006).
46. Lee, H. S., Park, J. H., Kim, S. J., Kwon, S. J. & Kwon, J. A cooperative activation loop among SWI/SNF, γ-H2AX and H3 acetylation for DNA double-strand break repair. EMBO J. 29, 1434-1445 (2010).
47. Zhang, Z. K. et al. Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5. Mol. Cell. Biol. 22, 5975-5988 (2002).
48. Wilson, B. G. & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nature Rev. Cancer 11, 481-492 (2011).
49. Kia, S. K., Gorski, M. M., Giannakopoulos, S. & Verrijzer, C. P. SWI/SNF mediates polycomb eviction and epigenetic reprogramming of the INK4b-ARF-INK4a locus. Mol. Cell. Biol. 28, 3457-3464 (2008).
50. Zeng, W., Ball, A. R. Jr & Yokomori, K. HP1: heterochromatin binding proteins working the genome. Epigenetics 5, 287-292 (2010).
51. Lachner, M., O'Carroll, D., Rea, S., Mechtler, K. & Jenuwein, T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature 410, 116-120 (2001).
52. Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120-124 (2001).
53. Ayoub, N., Jeyasekharan, A. D., Bernal, J. A. & Venkitaraman, A. R. HP1-ß mobilization promotes chromatin changes that initiate the DNA damage response. Nature 453, 682-686 (2008).
54. Shanbhag, N. M., Rafalska-Metcalf, I. U., Balane-Bolivar, C, Janicki, S. M. & Greenberg, R. A. ATM-dependent chromatin changes silence transcription in cis to DNA double-strand breaks. Cell 141, 970-981 (2010).
55. Luijsterburg, M. S. et al. Heterochromatin protein 1 is recruited to various types of DNA damage. J. Cell Biol. 185, 577-586 (2009).
56. Zarebski, M., Wiernasz, E. & Dobrucki, J. W Recruitment of heterochromatin protein 1 to DNA repair sites. Cytometry A 75, 619-625 (2009).
57. Ayoub, N., Jeyasekharan, A. D. & Venkitaraman, A. R. Mobilization and recruitment of HP1: a bimodal response to DNA breakage. Cell Cycle 8, 2945-2950 (2009).
58. Baldeyron, C, Soria, G., Roche, D., Cook, A. J. & Almouzni, G. HP1 a recruitment to DNA damage by p150CAF-1 promotes homologous recombination repair. J. Cell Biol. 193, 81-95 (2011).
59. De Koning, L. et al. Heterochromatin protein 1 a: a hallmark of cell proliferation relevant to clinical oncology. EMBO Mol. Med. 1, 178-191 (2009).
60. Dialynas, G. K., Vitalini, M. W. & Wallrath, L. L. Linking Heterochromatin Protein 1 (HP1) to cancer progression. Mutat. Res. 647, 13-20 (2008).
61. Norwood, L. E. et al. A requirement for dimerization of HP1Hsa in suppression of breast cancer invasion. J. Biol. Chem. 281, 18668-18676 (2006).
62. Kirschmann, D. A. et al. Down-regulation of HP1Hsa expression is associated with the metastatic phenotype in breast cancer. Cancer Res. 60, 3359-3363 (2000).
63. Takanashi, M. et al. Heterochromatin protein 1y epigenetically regulates cell differentiation and exhibits potential as a therapeutic target for various types of cancers. Am. J. Pathol. 174, 309-316 (2009).
64. Decottignies, A. & dAdda di Fagagna, F Epigenetic alterations associated with cellular senescence: a barrier against tumorigenesis or a red carpet for cancer? Semin. Cancer Biol. 21, 360-366 (2011).
65. Burma, S., Chen, B. P., Murphy, M., Kurimasa, A. & Chen, D. J. ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J. Biol. Chem. 276, 42462-42467 (2001).
66. Stiff, T. et al. ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res. 64, 2390-2396 (2004).
67. Celeste, A. et al. Genomic instability in mice lacking histone H2AX. Science 296, 922-927 (2002).
68. Celeste, A. et al. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nature Cell Biol. 5, 675-679 (2003).
69. Celeste, A. et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114, 371-383 (2003).
70. Bassing, C. H. et al. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114, 359-370 (2003).
71. Nuciforo, P. G., Luise, C, Capra, M., Pelosi, G. & d'Adda di Fagagna, F Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression. Carcinogenesis 28, 2082-2088 (2007).
72. Bonner, W. M. et al. yH2AX and cancer. Nature Rev. Cancer 8, 957-967 (2008).
73. Novik, K. L. et al. Genetic variation in H2AFX contributes to risk of non-Hodgkin lymphoma. Cancer Epidemiol. Biomarkers Prev. 16, 1098-1106 (2007).
74. Liu, Y. et al. Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate. Cancer Res. 67, 2685-2692 (2007).
75. Xiao, A. et al. WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature 457, 57-62 (2009).
76. Cook, P. J. et al. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 458, 591-596 (2009).
77. Jacobs, J. J. et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13, 2678-2690 (1999).
78. Ginjala, V. et al. BMI1 is recruited to dna breaks and contributes to DNA damage-induced H2A ubiquitination and repair. Mol. Cell. Biol. 31, 1972-1982 (2011).
79. Ismail, I. H., Andrin, C., McDonald, D. & Hendzel, M. J. BMI1-mediated histone ubiquitylation promotes DNA double-strand break repair. J. Cell Biol. 191, 45-60 (2011).
80. Chagraoui, J., Hebert, J., Girard, S. & Sauvageau, G. An anticlastogenic function for the Polycomb Group gene Bmi1. Proc. Natl Acad. Sci. USA 108, 5284-5289 (2011).
81. Wang, E. et al. Enhancing chemotherapy response with Bmi-1 silencing in ovarian cancer. PLoS ONE 6, e17918 (2011).
82. Ikura, T. et al. DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Mol. Cell. Biol. 27, 7028-7040 (2007).
83. Stewart, G. S. et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136, 420-434 (2009).
84. Mailand, N. et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131, 887-900 (2007).
85. Wang, B. & Elledge, S. J. Ubc13/Rnf8 ubiquitin ligases control foci formation of the Rap80/Abraxas/Brca1/Brcc36 complex in response to DNA damage. Proc. Natl Acad. Sci. USA 104, 20759-20763 (2007).
86. Moyal, L. et al. Requirement of ATM-dependent monoubiquitylation of histone H2B for timely repair of dna double-strand breaks. Mol. Cell 41, 529-542 (2011).
87. Doil, C. et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 136, 435-446 (2009).
88. Wu, J. et al. Histone ubiquitination associates with BRCA1-dependent DNA damage response. Mol. Cell. Biol. 29, 849-860 (2009).
89. Sun, Y. et al. Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. Nature Cell Biol. 11, 1376-1382 (2009).
90. Fischle, W. et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438, 1116-1122 (2005).
91. Hirota, T., Lipp, J. J., Toh, B. H. & Peters, J. M. Histone H3 serine 10 phosphorylation by Aurora B causes HP1 dissociation from heterochromatin. Nature 438, 1176-1180 (2005).
92. Gorrini, C. et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448, 1063-1067 (2007).
93. Park, Y. S. et al. The global histone modification pattern correlates with cancer recurrence and overall survival in gastric adenocarcinoma. Ann. Surg. Oncol. 15, 1968-1976 (2008).
94. Muller-Tidow, C. et al. Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia. Blood 11 6, 3564-3571 (2010).
95. Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406-411 (2004).
96. Botuyan, M. V. et al. Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell 127, 1361-1373 (2006).
97. Oda, H. et al. Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage. Mol. Cell 40, 364-376 (2010).
98. Vidanes, G. M., Bonilla, C. Y. & Toczyski, D. P. Complicated tails: histone modifications and the DNA damage response. Cell 121, 973-976 (2005).
99. Pei, H. et al. MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 470, 124-128 (2011).
100. Yan, Q. et al. BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response. Mol. Cell 36, 110-120 (2009).
101. Schneider, A. C. et al. Global histone H4K20 trimethylation predicts cancer-specific survival in patients with muscle-invasive bladder cancer. BJU Int. 108, e290-e296 (2011).
102. Masumoto, H., Hawke, D., Kobayashi, R. & Verreault, A. A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response. Nature 436, 294-298 (2005).
103. Chen, C. C. et al. Acetylated lysine 56 on histone H3 drives chromatin assembly after repair and signals for the completion of repair. Cell 134, 231-243 (2008).
104. Celic, I. et al. The sirtuins hst3 and Hst4p preserve genome integrity by controlling histone h3 lysine 56 deacetylation. Curr. Biol. 16, 1280-1289 (2006).
105. Driscoll, R., Hudson, A. & Jackson, S. P. Yeast Rtt109 promotes genome stability by acetylating histone H3 on lysine 56. Science 315, 649-652 (2007).
106. Tjeertes, J. V., Miller, K. M. & Jackson, S. P. Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cells. EMBO J. 28, 1878-1889 (2009).
107. Yuan, J., Pu, M., Zhang, Z. & Lou, Z. Histone H3-K56 acetylation is important for genomic stability in mammals. Cell Cycle 8, 1747-1753 (2009).
108. Miller, K. M. et al. Human HDAC1 and HDAC2 function in the DNA-damage response to promote DNA nonhomologous end-joining. Nature Struct. Mol. Biol. 17, 1144-1151 (2010).
109. Das, C., Lucia, M. S., Hansen, K. C. & Tyler, J. K. CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature 459, 113-117 (2009).
110. Murr, R. et al. Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nature Cell Biol. 8, 91-99 (2006).
111. Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463-473 (2000).
112. Miyamoto, N. et al. Tip60 is regulated by circadian transcription factor clock and is involved in cisplatin resistance. J. Biol. Chem. 283, 18218-18226 (2008).
113. Suram, A. et al. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 31, 2839-2851 (2012).
114. Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 11 3, 703-716 (2003).
115. Zhang, R., Chen, W. & Adams, P. D. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol. Cell. Biol. 27, 2343-2358 (2007).
116. Ye, X. et al. Definition of pRB-and p53-dependent and-independent steps in HIRA/ASF1a-mediated formation of senescence-associated heterochromatin foci. Mol. Cell. Biol. 27, 2452-2465 (2007).
117. Toledo, L. I., Murga, M., Gutierrez-Martinez, P., Soria, R. & Fernandez-Capetillo, O. ATR signaling can drive cells into senescence in the absence of DNA breaks. Genes Dev. 22, 297-302 (2008).
118. Jasencakova, Z. et al. Replication stress interferes with histone recycling and predeposition marking of new histones. Mol. Cell 37, 736-743 (2010).
119. Stillman, B. Chromatin assembly during SV40 DNA replication in vitro. Cell 45, 555-565 (1986).
120. Mello, J. A. et al. Human Asf1 and CAF-1 interact and synergize in a repair-coupled nucleosome assembly pathway. EMBO Rep. 3, 329-334 (2002).
121. Myung, K., Pennaneach, V., Kats, E. S. & Kolodner, R. D. Saccharomyces cerevisiae chromatin-assembly factors that act during DNA replication function in the maintenance of genome stability. Proc. Natl Acad. Sci. USA 100, 6640-6645 (2003).
122. Ye, X. et al. Defective S phase chromatin assembly causes DNA damage, activation of the S phase checkpoint, and S phase arrest. Mol. Cell 11, 341-351 (2003).
123. Singh, G. & Klar, A. J. Mutations in deoxyribonucleotide biosynthesis pathway cause spreading of silencing across heterochromatic barriers at the mating-type region of the fission yeast. Yeast 25, 117-128 (2008).
124. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660-665 (2005).
125. Kosar, M. et al. Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type-and insult-dependent manner and follow expression of p16(ink4a). Cell Cycle 10, 457-468 (2011).
126. Corpet, A. et al. Asf1b, the necessary Asf1 isoform for proliferation, is predictive of outcome in breast cancer. EMBO J. 30, 480-493 (2011).
127. Kang, M. Y. et al. Association of the SUV39H1 histone methyltransferase with the DNA methyltransferase 1 at mRNA expression level in primary colorectal cancer. Int. J. Cancer 121, 2192-2197 (2007).
128. Bandyopadhyay, D. et al. Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes. Cancer Res. 62, 6231-6239 (2002).
129. Adams, P. D. Remodeling chromatin for senescence. Aging Cell 6, 425-427 (2007).
130. Ye, X. et al. Downregulation of Wnt signaling is a trigger for formation of facultative heterochromatin and onset of cell senescence in primary human cells. Mol. Cell 27, 183-196 (2007).
131. Funayama, R., Saito, M., Tanobe, H. & Ishikawa, F. Loss of linker histone H1 in cellular senescence. J. Cell Biol. 175, 869-880 (2006).
132. O'Sullivan, R. J., Kubicek, S., Schreiber, S. L. & Karlseder, J. Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres. Nature Struct. Mol. Biol. 17, 1218-1225 (2010).
133. Narita, M. et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 126, 503-514 (2006).
134. Adams, P. D. Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging. Gene 397, 84-93 (2007).
135. Sporn, J. C. et al. Histone macroH2A isoforms predict the risk of lung cancer recurrence. Oncogene 28, 3423-3428 (2009).
136. Minucci, S. & Pelicci, P. G. Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nature Rev. Cancer 6, 38-51 (2006).
137. Johnstone, R. W. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature Rev. Drug Discov. 1, 287-299 (2002).
138. Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69-80 (2010).
139. Karagiannis, T. C. & El-Osta, A. Modulation of cellular radiation responses by histone deacetylase inhibitors. Oncogene 25, 3885-3893 (2006).
140. Camphausen, K. & Tofilon, P. J. Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J. Clin. Oncol. 25, 4051-4056 (2007).
141. Aniello, F. et al. Expression of four histone lysine-methyltransferases in parotid gland tumors. Anticancer Res. 26, 2063-2067 (2006).
142. Chang, M. J. et al. Histone H3 lysine 79 methyl-transferase Dot1 is required for immortalization by MLL oncogenes. Cancer Res. 70, 10234-10242 (2010).
143. Guenther, M. G. et al. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. Genes Dev. 22, 3403-3408 (2008).
144. Bernt, K. M. et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66-78 (2011).
145. Lin, Y. H. et al. Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias. Blood 11 4, 651-658 (2009).
146. Daigle, S. R. et al. Selective killing of mixed lineage leukemia cells by a potent small-molecule DOT1L inhibitor. Cancer Cell 20, 53-65 (2011).
147. Ward, I. M. & Chen, J. Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J. Biol. Chem. 276, 47759-47762 (2001).
148. Francia, S. et al. Site-specific DICER and DROSHA RNA products control the DNA-damage response. Nature 488, 231-235 (2012).