MMSET Regulates Histone H4K20 Methylation and 53BP1 Accumulation at DNA Damage Sites

Overview

Journal Nature

Specialty Science

Date 2011 Feb 5

PMID 21293379

Citations 239

Authors

Huadong Pei

Lindsey Zhang

Kuntian Luo

Yuxin Qin

Marta Chesi

Frances Fei

P Leif Bergsagel

Liewei Wang

Zhongsheng You

Zhenkun Lou

Affiliations

Soon will be listed here.

Abstract

p53-binding protein 1 (53BP1) is known to be an important mediator of the DNA damage response, with dimethylation of histone H4 lysine 20 (H4K20me2) critical to the recruitment of 53BP1 to double-strand breaks (DSBs). However, it is not clear how 53BP1 is specifically targeted to the sites of DNA damage, as the overall level of H4K20me2 does not seem to increase following DNA damage. It has been proposed that DNA breaks may cause exposure of methylated H4K20 previously buried within the chromosome; however, experimental evidence for such a model is lacking. Here we found that H4K20 methylation actually increases locally upon the induction of DSBs and that methylation of H4K20 at DSBs is mediated by the histone methyltransferase MMSET (also known as NSD2 or WHSC1) in mammals. Downregulation of MMSET significantly decreases H4K20 methylation at DSBs and the subsequent accumulation of 53BP1. Furthermore, we found that the recruitment of MMSET to DSBs requires the γH2AX-MDC1 pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated Ser 102 of MMSET. Thus, we propose that a pathway involving γH2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around DSBs, which, in turn, facilitates 53BP1 recruitment.

Citing Articles

The oncogenic role of the NSD histone methyltransferases in head and neck and cervical cancers.

Ghiani L, Chiocca S Tumour Virus Res. 2024; 19:200301.

PMID: 39645166 PMC: 11683330. DOI: 10.1016/j.tvr.2024.200301.

Identification of potential methyltransferase NSD2 enzymatic inhibitors through a multi-step structure-based drug design.

Shen Y, Zhang Y, Wu T, Zhang L, Belviso B Mol Divers. 2024; .

PMID: 39644397 DOI: 10.1007/s11030-024-11072-8.

DTX3L-mediated TIRR nuclear export and degradation regulates DNA repair pathway choice and PARP inhibitor sensitivity.

Ye Q, Ma J, Wang Z, Liu T, Wang B, Zhu L Nat Commun. 2024; 15(1):10596.

PMID: 39632881 PMC: 11618752. DOI: 10.1038/s41467-024-54978-5.

VGLL3 modulates chemosensitivity through promoting DNA double-strand break repair.

Wu W, Fan Z, Fu H, Ma X, Wang D, Liu H Sci Adv. 2024; 10(41):eadr2643.

PMID: 39383226 PMC: 11463272. DOI: 10.1126/sciadv.adr2643.

Unveiling the potential of phytochemicals to inhibit nuclear receptor binding SET domain protein 2 for cancer: Pharmacophore screening, molecular docking, ADME properties, and molecular dynamics simulation investigations.

Mohamed G, Abdallah H, Sindi I, Ibrahim S, Alzain A PLoS One. 2024; 19(8):e0308913.

PMID: 39163297 PMC: 11335128. DOI: 10.1371/journal.pone.0308913.

References

Yu X, Chini C, He M, Mer G, Chen J . The BRCT domain is a phospho-protein binding domain. Science. 2003; 302(5645):639-42. DOI: 10.1126/science.1088753. View

Kim J, Kee H, Choe N, Kim S, Eom G, Baek H . Multiple-myeloma-related WHSC1/MMSET isoform RE-IIBP is a histone methyltransferase with transcriptional repression activity. Mol Cell Biol. 2008; 28(6):2023-34. PMC: 2268398. DOI: 10.1128/MCB.02130-07. View

Matsuoka S, Ballif B, Smogorzewska A, McDonald 3rd E, Hurov K, Luo J . ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science. 2007; 316(5828):1160-6. DOI: 10.1126/science.1140321. View

Stucki M, Clapperton J, Mohammad D, Yaffe M, Smerdon S, Jackson S . MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell. 2005; 123(7):1213-26. DOI: 10.1016/j.cell.2005.09.038. View

Kolas N, Chapman J, Nakada S, Ylanko J, Chahwan R, Sweeney F . Orchestration of the DNA-damage response by the RNF8 ubiquitin ligase. Science. 2007; 318(5856):1637-40. PMC: 2430610. DOI: 10.1126/science.1150034. View

Mailand N, Bekker-Jensen S, Faustrup H, Melander F, Bartek J, Lukas C . RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell. 2007; 131(5):887-900. DOI: 10.1016/j.cell.2007.09.040. View

Nishioka K, Rice J, Sarma K, Erdjument-Bromage H, Werner J, Wang Y . PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol Cell. 2002; 9(6):1201-13. DOI: 10.1016/s1097-2765(02)00548-8. View

Du L, Nakamura T, Russell P . Histone modification-dependent and -independent pathways for recruitment of checkpoint protein Crb2 to double-strand breaks. Genes Dev. 2006; 20(12):1583-96. PMC: 1482479. DOI: 10.1101/gad.1422606. View

Schotta G, Lachner M, Sarma K, Ebert A, Sengupta R, Reuter G . A silencing pathway to induce H3-K9 and H4-K20 trimethylation at constitutive heterochromatin. Genes Dev. 2004; 18(11):1251-62. PMC: 420351. DOI: 10.1101/gad.300704. View

10.

Marango J, Shimoyama M, Nishio H, Meyer J, Min D, Sirulnik A . The MMSET protein is a histone methyltransferase with characteristics of a transcriptional corepressor. Blood. 2007; 111(6):3145-54. PMC: 2265454. DOI: 10.1182/blood-2007-06-092122. View

11.

Kim J, Chen J, Lou Z . DBC1 is a negative regulator of SIRT1. Nature. 2008; 451(7178):583-6. DOI: 10.1038/nature06500. View

12.

Nimura K, Ura K, Shiratori H, Ikawa M, Okabe M, Schwartz R . A histone H3 lysine 36 trimethyltransferase links Nkx2-5 to Wolf-Hirschhorn syndrome. Nature. 2009; 460(7252):287-91. DOI: 10.1038/nature08086. View

13.

Moynahan M, Pierce A, Jasin M . BRCA2 is required for homology-directed repair of chromosomal breaks. Mol Cell. 2001; 7(2):263-72. DOI: 10.1016/s1097-2765(01)00174-5. View

14.

Botuyan M, Lee J, Ward I, Kim J, Thompson J, Chen J . Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair. Cell. 2006; 127(7):1361-73. PMC: 1804291. DOI: 10.1016/j.cell.2006.10.043. View

15.

Huen M, Grant R, Manke I, Minn K, Yu X, Yaffe M . RNF8 transduces the DNA-damage signal via histone ubiquitylation and checkpoint protein assembly. Cell. 2007; 131(5):901-14. PMC: 2149842. DOI: 10.1016/j.cell.2007.09.041. View

16.

Wang B, Matsuoka S, Carpenter P, Elledge S . 53BP1, a mediator of the DNA damage checkpoint. Science. 2002; 298(5597):1435-8. DOI: 10.1126/science.1076182. View

17.

Celeste A, Fernandez-Capetillo O, Kruhlak M, Pilch D, Staudt D, Lee A . Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol. 2003; 5(7):675-9. DOI: 10.1038/ncb1004. View

18.

Stec I, Wright T, van Ommen G, de Boer P, van Haeringen A, Moorman A . WHSC1, a 90 kb SET domain-containing gene, expressed in early development and homologous to a Drosophila dysmorphy gene maps in the Wolf-Hirschhorn syndrome critical region and is fused to IgH in t(4;14) multiple myeloma. Hum Mol Genet. 1998; 7(7):1071-82. DOI: 10.1093/hmg/7.7.1071. View

19.

You Z, Shi L, Zhu Q, Wu P, Zhang Y, Basilio A . CtIP links DNA double-strand break sensing to resection. Mol Cell. 2010; 36(6):954-69. PMC: 2807415. DOI: 10.1016/j.molcel.2009.12.002. View

20.

Fang J, Feng Q, Ketel C, Wang H, Cao R, Xia L . Purification and functional characterization of SET8, a nucleosomal histone H4-lysine 20-specific methyltransferase. Curr Biol. 2002; 12(13):1086-99. DOI: 10.1016/s0960-9822(02)00924-7. View