Sumoylation of MDC1 is important for proper DNA damage response.
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.
Key Laboratory of Arrhythmia, Ministry of Education, East Hospital, Tongji University School of Medicine, Shanghai, China.
Kuntian
K
Luo
Haoxing
H
Zhang
Liewei
L
Wang
Jian
J
Yuan
Zhenkun
Z
Lou
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D004249:DNA Damage; D015536:Down-Regulation; D004706:Endodeoxyribonucleases; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism; D059767:Recombinational DNA Repair; D051716:Replication Protein A / Q000378:metabolism; D058207:Sumoylation; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; C114070:RNF4 protein, human; C497167:RPA1 protein, human; D051716:Replication Protein A; C498301:TP53BP1 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human; D008239:Lysine