Journal
EMBO JOURNAL
Volume 31, Issue 13, Pages 3008-3019Publisher
WILEY
DOI: 10.1038/emboj.2012.158
Keywords
homologous recombination; MDC1; RNF4; sumoylation; ubiquitination
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Funding
- NIH [CA130996, CA151329]
- National Natural Science Foundation of China [81102011, 81101514]
- Program for New Century Excellent Talents in University [NCET-11-0388]
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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. The EMBO Journal (2012) 31, 3008-3019. doi: 10.1038/emboj.2012.158; Published online 25 May 2012
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