Publication Date:
2011-02-05
Description:
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 gammaH2AX-MDC1 pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated Ser 102 of MMSET. Thus, we propose that a pathway involving gammaH2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around DSBs, which, in turn, facilitates 53BP1 recruitment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064261/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064261/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pei, Huadong -- Zhang, Lindsey -- Luo, Kuntian -- Qin, Yuxin -- Chesi, Marta -- Fei, Frances -- Bergsagel, P Leif -- Wang, Liewei -- You, Zhongsheng -- Lou, Zhenkun -- CA130996/CA/NCI NIH HHS/ -- CA151329/CA/NCI NIH HHS/ -- R01 AG020686/AG/NIA NIH HHS/ -- R01 AG020686-06A2/AG/NIA NIH HHS/ -- R01 AG020686-07/AG/NIA NIH HHS/ -- R01 CA130996/CA/NCI NIH HHS/ -- R01 CA130996-03/CA/NCI NIH HHS/ -- R01 CA133966/CA/NCI NIH HHS/ -- R01 CA133966-01A2/CA/NCI NIH HHS/ -- R01 CA133966-02/CA/NCI NIH HHS/ -- R01 CA133966-03/CA/NCI NIH HHS/ -- R01 CA136671/CA/NCI NIH HHS/ -- R01 CA136671-02/CA/NCI NIH HHS/ -- R01 CA136671-03/CA/NCI NIH HHS/ -- R01 CA151329/CA/NCI NIH HHS/ -- R01 CA151329-01/CA/NCI NIH HHS/ -- R56 AG020686/AG/NIA NIH HHS/ -- R56 AG020686-06A1/AG/NIA NIH HHS/ -- England -- Nature. 2011 Feb 3;470(7332):124-8. doi: 10.1038/nature09658.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21293379" target="_blank"〉PubMed〈/a〉
Keywords:
Ataxia Telangiectasia Mutated Proteins
;
Cell Cycle Proteins/metabolism
;
Chromatin Immunoprecipitation
;
*DNA Breaks, Double-Stranded
;
DNA-Binding Proteins/metabolism
;
HEK293 Cells
;
HeLa Cells
;
Histone-Lysine N-Methyltransferase/chemistry/*metabolism
;
Histones/*chemistry/*metabolism
;
Humans
;
Intracellular Signaling Peptides and Proteins/*metabolism
;
Lysine/*metabolism
;
Methylation
;
Nuclear Proteins/chemistry/metabolism
;
Phosphorylation
;
Phosphoserine/metabolism
;
Protein Transport
;
Protein-Serine-Threonine Kinases/metabolism
;
Repressor Proteins/chemistry/*metabolism
;
Trans-Activators/chemistry/metabolism
;
Tumor Suppressor Proteins/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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