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PMID: 22635276 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Sumoylation of MDC1 is important for proper DNA damage response.

The EMBO journal ·Vol. 31 ·No. 13 ·2012-06-29 ·Pages 3008-19

Luo K, Zhang H, Wang L, Yuan J, Lou Z

Abstract

In response to DNA damage, many DNA damage factors, such as MDC1 and 53BP1, redistribute to sites of DNA damage. The mechanism governing the turnover of these factors at DNA damage sites, however, remains enigmatic. Here, we show that MDC1 is sumoylated following DNA damage, and the sumoylation of MDC1 at Lys1840 is required for MDC1 degradation and removal of MDC1 and 53BP1 from sites of DNA damage. Sumoylated MDC1 is recognized and ubiquitinated by the SUMO-targeted E3 ubiquitin ligase RNF4. Mutation of the MDC1 Lys 1840 (K1840R) results in impaired CtIP, replication protein A, and Rad51 accumulation at sites of DNA damage and defective homologous recombination (HR). The HR defect caused by MDC1K1840R mutation could be rescued by 53BP1 downregulation. These results reveal the intricate dynamics governing the assembly and disassembly of DNA damage factors at sites of DNA damage for prompt response to DNA damage.

MeSH Terms
Adaptor Proteins, Signal Transducing Carrier Proteins/metabolism Cell Cycle Proteins DNA Damage Down-Regulation Endodeoxyribonucleases HEK293 Cells HeLa Cells Humans Intracellular Signaling Peptides and Proteins/metabolism Lysine/metabolism Mutation Nuclear Proteins/genetics,metabolism Rad51 Recombinase/metabolism Recombinational DNA Repair Replication Protein A/metabolism Sumoylation Trans-Activators/genetics,metabolism Transcription Factors/metabolism Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases/metabolism
Chemicals
Adaptor Proteins, Signal Transducing Carrier Proteins Cell Cycle Proteins Intracellular Signaling Peptides and Proteins MDC1 protein, human Nuclear Proteins RNF4 protein, human RPA1 protein, human Replication Protein A TP53BP1 protein, human Trans-Activators Transcription Factors Tumor Suppressor p53-Binding Protein 1 Ubiquitin-Protein Ligases RAD51 protein, human Rad51 Recombinase Endodeoxyribonucleases RBBP8 protein, human Lysine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Luo Kuntian
Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai, China.
Zhang Haoxing
Wang Liewei
Yuan Jian
Lou Zhenkun
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2012.158
Published
2012-06-29
Epub
2012-00-25
Pages
3008-19
Language
English
Region
England
NLM ID
8208664
PMCID
PMC3395099
Subset
IM
Grants
NCI NIH HHS · R01 CA151329 · United States
NCI NIH HHS · R01 CA130996 · United States
NCI NIH HHS · R01 CA148940 · United States
NCI NIH HHS · CA151329 · United States
NCI NIH HHS · CA130996 · United States
External Links
PubMed source DOI: 10.1038/emboj.2012.158 PMC Full Text View journal details
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