4.7 Article

SLFN11 inhibits checkpoint maintenance and homologous recombination repair

Journal

EMBO REPORTS
Volume 17, Issue 1, Pages 94-109

Publisher

WILEY-BLACKWELL
DOI: 10.15252/embr.201540964

Keywords

checkpoint initiation; checkpoint maintenance; DNA damage response; homologous recombination repair; RPA

Funding

  1. National Basic Research Program of China [2012CB944402, 2013CB911003, 2013CB945303]
  2. National Program for Special Support of Eminent Professionals
  3. National Natural Science Funds for Distinguished Young Scholar
  4. National Natural Science Foundation of China [31071243, 31171347]
  5. China's Fundamental Research Funds for the Central Universities
  6. Research Fund for the Doctoral Program of Higher Education [20110101120152]

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High expression levels of SLFN11 correlate with the sensitivity of human cancer cells to DNA-damaging agents. However, little is known about the underlying mechanism. Here, we show that SLFN11 interacts directly with RPA1 and is recruited to sites of DNA damage in an RPA1-dependent manner. Furthermore, we establish that SLFN11 inhibits checkpoint maintenance and homologous recombination repair by promoting the destabilization of the RPA-ssDNA complex, thereby sensitizing cancer cell lines expressing high endogenous levels of SLFN11 to DNA-damaging agents. Finally, we demonstrate that the RPA1-binding ability of SLFN11 is required for its function in the DNA damage response. Our findings not only provide novel insight into the molecular mechanisms underlying the drug sensitivity of cancer cell lines expressing SLFN11 at high levels, but also suggest that SLFN11 expression can serve as a biomarker to predict responses to DNA-damaging therapeutic agents.

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