Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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BRCA1 Protein / metabolism
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Cell Cycle / genetics
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Cell Cycle Proteins
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Cell Nucleus / chemistry
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Chromatin / chemistry
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Chromatin / metabolism*
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DNA Repair*
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DNA-Binding Proteins / analysis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Enzyme Stability
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Gene Silencing
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Humans
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Nuclear Proteins / analysis
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Rad51 Recombinase / metabolism*
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Radiation Tolerance*
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Radiation, Ionizing
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Recombination, Genetic*
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Trans-Activators / analysis
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Trans-Activators / genetics
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Trans-Activators / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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BRCA1 Protein
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Cell Cycle Proteins
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Chromatin
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DNA-Binding Proteins
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MDC1 protein, human
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Nuclear Proteins
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Trans-Activators
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RAD51 protein, human
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Rad51 Recombinase