MDC1 interacts with Rad51 and facilitates homologous recombination.
Mediator of DNA damage checkpoint protein-1 (MDC1) is a recently identified nuclear protein that participates in DNA-damage sensing and signaling. Here we report that knockdown of MDC1 by RNA interference results in cellular hypersensitivity to the DNA cross-linking agent mitomycin C and ionizing radiation and in impaired homology-mediated repair of double-strand breaks in DNA. MDC1 forms a complex with Rad51 through a direct interaction with the forkhead-associated domain of MDC1, not the BRCA1 C-terminal domain. Depletion of MDC1 results in impaired formation of Rad51 ionizing radiation-induced foci, reduced amounts of nuclear and chromatin-bound Rad51, and a corresponding increase in Rad51 protein degradation. Together, our findings suggest that MDC1 functions in Rad51-mediated homologous recombination by retaining Rad51 in chromatin.
Zhang
Junran
J
Department of Radiation Oncology, MGH Cancer Center, Massachusetts General Hospital and Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA.
Ma
Zhefu
Z
Treszezamsky
Alejandro
A
Powell
Simon N
SN
D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D002467:Cell Nucleus / Q000737:chemistry; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D004795:Enzyme Stability; D020868:Gene Silencing; D006801:Humans; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D011995:Recombination, Genetic; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C413163:MDC1 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; C495153:RAD51 protein, human; D051135:Rad51 Recombinase