Journal Article

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

Chesi, Marta, Pei, Huadong, Zhang, Lindsey, Fei, Frances, You, Zhongsheng, Bergsagel, P. Leif, Wang, Liewei, Lou, Zhenkun, Qin, Yuxin, Luo, Kuntian

2011

Overview

DNA-repair pathways defined Recruitment of p53 binding protein 1 (53BP1) to double-strand DNA breaks is an important step in the cellular response to DNA damage. Here, the histone methyltransferase MMSET is shown to be responsible for localized increases in a histone modification that is involved in recruiting 53BP1. The mechanism of MMSET recruitment to DNA damage sites is also investigated. Recruitment of 53BP1 to double-strand DNA breaks is an important step in the cellular response to DNA damage. Here, the histone methyltransferase MMSET is shown to be responsible for localized increases in a histone modification that is involved in recruiting 53BP1. The mechanism of MMSET recruitment to DNA damage sites is also investigated. p53-binding protein 1 (53BP1) is known to be an important mediator of the DNA damage response 1 , 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337/1427/2122 / 631/337/1427/2566 / 631/45/612/1238 / 692/699/67/1990/804 / Adaptor Proteins, Signal Transducing / Ataxia Telangiectasia Mutated Proteins / Binding sites / Biological and medical sciences / Cell Cycle Proteins - metabolism / Chromatin Immunoprecipitation / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded / DNA damage / DNA methylation / DNA-Binding Proteins - metabolism / Fundamental and applied biological sciences. Psychology / Genetic aspects / HEK293 Cells / HeLa Cells / Histone-Lysine N-Methyltransferase - chemistry / Histone-Lysine N-Methyltransferase - metabolism / Histones / Histones - chemistry / Histones - metabolism / Humanities and Social Sciences / Humans / Intracellular Signaling Peptides and Proteins - metabolism / letter / Lysine - metabolism / Management / Methylation / Molecular and cellular biology / Molecular genetics / multidisciplinary / Mutagenesis. Repair / Nuclear Proteins - chemistry / Nuclear Proteins - metabolism / Phosphorylation / Phosphoserine - metabolism / Physiological aspects / Protein Serine-Threonine Kinases - metabolism / Protein Transport / Proteins / Recruitment / Repressor Proteins - chemistry / Repressor Proteins - metabolism / Science / Science (multidisciplinary) / Studies / Trans-Activators - chemistry / Trans-Activators - metabolism / Tumor Suppressor p53-Binding Protein 1 / Tumor Suppressor Proteins - metabolism