Crosstalk between chromatin state and DNA damage response in cellular senescence and cancer
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Kornberg, R. D. Chromatin structure: a repeating unit of histones and DNA. Science 184, 868–871 (1974).
d'Adda di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nature Rev. Cancer 8, 512–522 (2008).
Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).
Di Micco, R. et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638–642 (2006).
Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633–637 (2006).
Lopez-Contreras, A. J. & Fernandez-Capetillo, O. The ATR barrier to replication-born DNA damage. DNA Repair 9, 1249–1255 (2010).
Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nature Cell Biol. 14, 355–365 (2012).
Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).
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).
Evan, G. I. & d'Adda di Fagagna, F. Cellular senescence: hot or what? Curr. Opin. Genet. Dev. 19, 25–31 (2009).
Jackson, S. P. & Bartek, J. The DNA-damage response in human biology and disease. Nature 461, 1071–1078 (2009).
Collado, M. & Serrano, M. The power and the promise of oncogene-induced senescence markers. Nature Rev. Cancer 6, 472–476 (2006).
Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).
Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).
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).
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).
Costes, S. V. et al. Image-based modeling reveals dynamic redistribution of DNA damage into nuclear sub-domains. PLoS Comput. Biol. 3, e155 (2007).
Cowell, I. G. et al. γH2AX foci form preferentially in euchromatin after ionising-radiation. PLoS ONE 2, e1057 (2007).
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).
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).
Murga, M. et al. Global chromatin compaction limits the strength of the DNA damage response. J. Cell Biol. 178, 1101–1108 (2007).
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).
Goodarzi, A. A. et al. ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin. Mol. Cell 31, 167–177 (2008).
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).
Denslow, S. A. & Wade, P. A. The human Mi-2/NuRD complex and gene regulation. Oncogene 26, 5433–5438 (2007).
Yokoe, T. et al. KAP1 is associated with peritoneal carcinomatosis in gastric cancer. Ann. Surg. Oncol. 17, 821–828 (2010).
Ho, J. et al. Novel breast cancer metastasis-associated proteins. J. Proteome Res. 8, 583–594 (2009).
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).
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).
Soutoglou, E. et al. Positional stability of single double-strand breaks in mammalian cells. Nature Cell Biol. 9, 675–682 (2007).
Pentimalli, F. et al. HMGA1 protein is a novel target of the ATM kinase. Eur. J. Cancer 44, 2668–2679 (2008).
Palmieri, D. et al. HMGA proteins promote ATM expression and enhance cancer cell resistance to genotoxic agents. Oncogene 30, 3024–3035 (2011).
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 119, 777–788 (2004).
Morrison, A. J. et al. INO80 and γ-H2AX interaction links ATP-dependent chromatin remodeling to DNA damage repair. Cell 119, 767–775 (2004).
Wu, S. et al. A YY1-INO80 complex regulates genomic stability through homologous recombination-based repair. Nature Struct. Mol. Biol. 14, 1165–1172 (2007).
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).
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).
Papamichos-Chronakis, M. & Peterson, C. L. The Ino80 chromatin-remodeling enzyme regulates replisome function and stability. Nature Struct. Mol. Biol. 15, 338–345 (2008).
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).
Dominguez-Sola, D. et al. Non-transcriptional control of DNA replication by c-Myc. Nature 448, 445–451 (2007).
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).
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).
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).
Zhang, Z. K. et al. Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5. Mol. Cell. Biol. 22, 5975–5988 (2002).
Wilson, B. G. & Roberts, C. W. SWI/SNF nucleosome remodellers and cancer. Nature Rev. Cancer 11, 481–492 (2011).
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).
Zeng, W., Ball, A. R. Jr & Yokomori, K. HP1: heterochromatin binding proteins working the genome. Epigenetics 5, 287–292 (2010).
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).
Bannister, A. J. et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature 410, 120–124 (2001).
Ayoub, N., Jeyasekharan, A. D., Bernal, J. A. & Venkitaraman, A. R. HP1-β mobilization promotes chromatin changes that initiate the DNA damage response. Nature 453, 682–686 (2008).
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).
Luijsterburg, M. S. et al. Heterochromatin protein 1 is recruited to various types of DNA damage. J. Cell Biol. 185, 577–586 (2009).
Zarebski, M., Wiernasz, E. & Dobrucki, J. W. Recruitment of heterochromatin protein 1 to DNA repair sites. Cytometry A 75, 619–625 (2009).
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).
Baldeyron, C., Soria, G., Roche, D., Cook, A. J. & Almouzni, G. HP1α recruitment to DNA damage by p150CAF-1 promotes homologous recombination repair. J. Cell Biol. 193, 81–95 (2011).
De Koning, L. et al. Heterochromatin protein 1α: a hallmark of cell proliferation relevant to clinical oncology. EMBO Mol. Med. 1, 178–191 (2009).
Dialynas, G. K., Vitalini, M. W. & Wallrath, L. L. Linking Heterochromatin Protein 1 (HP1) to cancer progression. Mutat. Res. 647, 13–20 (2008).
Norwood, L. E. et al. A requirement for dimerization of HP1Hsα in suppression of breast cancer invasion. J. Biol. Chem. 281, 18668–18676 (2006).
Kirschmann, D. A. et al. Down-regulation of HP1Hsα expression is associated with the metastatic phenotype in breast cancer. Cancer Res. 60, 3359–3363 (2000).
Takanashi, M. et al. Heterochromatin protein 1γ epigenetically regulates cell differentiation and exhibits potential as a therapeutic target for various types of cancers. Am. J. Pathol. 174, 309–316 (2009).
Decottignies, A. & d'Adda 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).
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).
Stiff, T. et al. ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Cancer Res. 64, 2390–2396 (2004).
Celeste, A. et al. Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nature Cell Biol. 5, 675–679 (2003).
Celeste, A. et al. H2AX haploinsufficiency modifies genomic stability and tumor susceptibility. Cell 114, 371–383 (2003).
Bassing, C. H. et al. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114, 359–370 (2003).
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).
Novik, K. L. et al. Genetic variation in H2AFX contributes to risk of non-Hodgkin lymphoma. Cancer Epidemiol. Biomarkers Prev. 16, 1098–1106 (2007).
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).
Xiao, A. et al. WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase activity. Nature 457, 57–62 (2009).
Cook, P. J. et al. Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 458, 591–596 (2009).
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).
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).
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).
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).
Wang, E. et al. Enhancing chemotherapy response with Bmi-1 silencing in ovarian cancer. PLoS ONE 6, e17918 (2011).
Ikura, T. et al. DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Mol. Cell. Biol. 27, 7028–7040 (2007).
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).
Mailand, N. et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 131, 887–900 (2007).
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).
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).
Doil, C. et al. RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to allow accumulation of repair proteins. Cell 136, 435–446 (2009).
Wu, J. et al. Histone ubiquitination associates with BRCA1-dependent DNA damage response. Mol. Cell. Biol. 29, 849–860 (2009).
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).
Fischle, W. et al. Regulation of HP1-chromatin binding by histone H3 methylation and phosphorylation. Nature 438, 1116–1122 (2005).
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).
Gorrini, C. et al. Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response. Nature 448, 1063–1067 (2007).
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).
Muller-Tidow, C. et al. Profiling of histone H3 lysine 9 trimethylation levels predicts transcription factor activity and survival in acute myeloid leukemia. Blood 116, 3564–3571 (2010).
Huyen, Y. et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature 432, 406–411 (2004).
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).
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).
Vidanes, G. M., Bonilla, C. Y. & Toczyski, D. P. Complicated tails: histone modifications and the DNA damage response. Cell 121, 973–976 (2005).
Pei, H. et al. MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 470, 124–128 (2011).
Yan, Q. et al. BBAP monoubiquitylates histone H4 at lysine 91 and selectively modulates the DNA damage response. Mol. Cell 36, 110–120 (2009).
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).
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).
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).
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).
Driscoll, R., Hudson, A. & Jackson, S. P. Yeast Rtt109 promotes genome stability by acetylating histone H3 on lysine 56. Science 315, 649–652 (2007).
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).
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).
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).
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).
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).
Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000).
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).
Suram, A. et al. Oncogene-induced telomere dysfunction enforces cellular senescence in human cancer precursor lesions. EMBO J. 31, 2839–2851 (2012).
Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003).
Zhang, R., Chen, W. & Adams, P. D. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol. Cell. Biol. 27, 2343–2358 (2007).
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).
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).
Jasencakova, Z. et al. Replication stress interferes with histone recycling and predeposition marking of new histones. Mol. Cell 37, 736–743 (2010).
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).
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).
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).
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).
Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005).
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).
Corpet, A. et al. Asf1b, the necessary Asf1 isoform for proliferation, is predictive of outcome in breast cancer. EMBO J. 30, 480–493 (2011).
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).
Bandyopadhyay, D. et al. Down-regulation of p300/CBP histone acetyltransferase activates a senescence checkpoint in human melanocytes. Cancer Res. 62, 6231–6239 (2002).
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).
Funayama, R., Saito, M., Tanobe, H. & Ishikawa, F. Loss of linker histone H1 in cellular senescence. J. Cell Biol. 175, 869–880 (2006).
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).
Narita, M. et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell 126, 503–514 (2006).
Adams, P. D. Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging. Gene 397, 84–93 (2007).
Sporn, J. C. et al. Histone macroH2A isoforms predict the risk of lung cancer recurrence. Oncogene 28, 3423–3428 (2009).
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).
Johnstone, R. W. Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nature Rev. Drug Discov. 1, 287–299 (2002).
Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
Karagiannis, T. C. & El-Osta, A. Modulation of cellular radiation responses by histone deacetylase inhibitors. Oncogene 25, 3885–3893 (2006).
Camphausen, K. & Tofilon, P. J. Inhibition of histone deacetylation: a strategy for tumor radiosensitization. J. Clin. Oncol. 25, 4051–4056 (2007).
Aniello, F. et al. Expression of four histone lysine-methyltransferases in parotid gland tumors. Anticancer Res. 26, 2063–2067 (2006).
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).
Guenther, M. G. et al. Aberrant chromatin at genes encoding stem cell regulators in human mixed-lineage leukemia. Genes Dev. 22, 3403–3408 (2008).
Bernt, K. M. et al. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 20, 66–78 (2011).
Lin, Y. H. et al. Global reduction of the epigenetic H3K79 methylation mark and increased chromosomal instability in CALM-AF10-positive leukemias. Blood 114, 651–658 (2009).
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).
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).