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MDC1 interacts with Rad51 and facilitates homologous recombination

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.

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Figure 1: MDC1 is involved in DNA damage response to MMC and ionizing radiation (IR).
Figure 2: Impaired I-SceI–induced homologous recombination in MDC1-deficient cells.
Figure 3: Association of MDC1 and Rad51.
Figure 4: Rad51 IRIF are deficient in MDC1-knockdown cells at early time points after exposure to ionizing radiation (IR).
Figure 5: Reduction of nuclear and chromatin-bound Rad51 protein after MDC1 siRNA transfection.
Figure 6: Decreased Rad51 protein stability in cells with MDC1 knockdown.

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Acknowledgements

We thank J. Chen and M. Jasin for their generous contribution of materials. This work was supported by Public Health Science grant CA107640 to S.N.P.

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Correspondence to Simon N Powell.

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Zhang, J., Ma, Z., Treszezamsky, A. et al. MDC1 interacts with Rad51 and facilitates homologous recombination. Nat Struct Mol Biol 12, 902–909 (2005). https://doi.org/10.1038/nsmb991

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