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MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites

Nature volume 470, pages 124–128 (2011)Cite this article

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Abstract

p53-binding protein 1 (53BP1) is known to be an important mediator of the DNA damage response1, with dimethylation of histone H4 lysine 20 (H4K20me2) critical to the recruitment of 53BP1 to double-strand breaks (DSBs)2,3. 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.

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Figure 1: Induction of H4K20 methylation and recruitment of MMSET at DSBs.
Figure 2: MMSET is required for H4K20me2/3 and 53BP1 accumulation at DSBs.
Figure 3: Recruitment of MMSET to DSBs requires the ATM–H2AX–MDC1 pathway.
Figure 4: Phosphorylation of MMSET is important for H4K20 methylation, 53BP1 recruitment and the DNA damage response.

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Acknowledgements

We thank M. Jasin for providing HeLa DR–GFP cells, and S. Baylin for providing MDA-MB-231 cells with inducible I-SceI expression. We thank M. Goldberg, X. Yu and M. Stucki for providing MDC1 and BRCA1 constructs. We thank M. Huen for providing 53BP1 expression constructs. We thank J. D. Licht for providing MMSET antibodies and B. Ho Park for providing MMSET shRNAs. This work was supported by the Richard Schulze Family Foundation and the NIH (CA130996 and CA151329; Z.L.), a grant from the American Cancer Society (IRG-58-010-52; Z.Y.) and a Siteman Career Award in Breast Cancer Research (Z.Y.).

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Author notes

  1. Lindsey Zhang and Kuntian Luo: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Oncology Research, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Huadong Pei, Kuntian Luo & Zhenkun Lou

  2. Department of Cell Biology and Physiology, Washington University, St Louis, 63110, Missouri, USA

    Lindsey Zhang, Frances Fei & Zhongsheng You

  3. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Yuxin Qin & Liewei Wang

  4. Comprehensive Cancer Center, Mayo Clinic Arizona, Scottsdale, 85259, Arizona, USA

    Marta Chesi & P. Leif Bergsagel

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Contributions

H.P. designed and performed the experiments; L.Z., K.L., Y.Q. and F.F. performed some experiments; M.C. and P.L.B. provided essential tools; L.W., Z.Y. and Z.L. designed the experiments and supervised the project.

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Correspondence to Zhenkun Lou.

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The authors declare no competing financial interests.

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Pei, H., Zhang, L., Luo, K. et al. MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites. Nature 470, 124–128 (2011). https://doi.org/10.1038/nature09658

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