title: MMSET regulates histone H4K20 methylation and 53BP1 accumulation at DNA damage sites.
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.
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Huadong
authors.initials: H
authors.lastname: Pei
authors.forename: Lindsey
authors.initials: L
authors.lastname: Zhang
authors.forename: Kuntian
authors.initials: K
authors.lastname: Luo
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Qin
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.forename: Frances
authors.initials: F
authors.lastname: Fei
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: Liewei
authors.initials: L
authors.lastname: Wang
authors.forename: Zhongsheng
authors.initials: Z
authors.lastname: You
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000378:metabolism*; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; D010768:Phosphoserine; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D008239:Lysine