4.8 Article

DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities

Journal

MOLECULAR CELL
Volume 53, Issue 1, Pages 7-18

Publisher

CELL PRESS
DOI: 10.1016/j.molcel.2013.11.003

Keywords

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Funding

  1. National Institutes of Health [CA117638]
  2. National Cancer Institute [P01 CA092584]
  3. Netherlands Organization for Scientific Research [VICI 700.56.441]
  4. U.S. Department of Energy program Integrated Diffraction Analysis Technologies (IDAT)
  5. CIHR
  6. Medical Research Council
  7. Association for International Cancer Research
  8. Department of Health
  9. Wellcome Trust
  10. NATIONAL CANCER INSTITUTE [P01CA092584, R01CA117638] Funding Source: NIH RePORTER
  11. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM105404] Funding Source: NIH RePORTER
  12. Medical Research Council [G0800005] Funding Source: researchfish
  13. MRC [G0800005] Funding Source: UKRI

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MRE11 within the MRE11-RAD50-NBS1 (MRN) complex acts in DNA double-strand break repair (DSBR), detection, and signaling; yet, how its endo- and exonuclease activities regulate DSBR by non-homologous end-joining (NHEJ) versus homologous recombination (HR) remains enigmatic. Here, we employed structure-based design with a focused chemical library to discover specific MRE11 endo- or exonuclease inhibitors. With these inhibitors, we examined repair pathway choice at DSBs generated in G2 following radiation exposure. While nuclease inhibition impairs radiation-induced replication protein A (RPA) chromatin binding, suggesting diminished resection, the inhibitors surprisingly direct different repair outcomes. Endonuclease inhibition promotes NHEJ in lieu of HR, while exonuclease inhibition confers a repair defect. Collectively, the results describe nuclease-specific MRE11 inhibitors, define distinct nuclease roles in DSB repair, and support a mechanism whereby MRE11 endonuclease initiates resection, thereby licensing HR followed by MRE11 exonuclease and EXO1/BLM bidirectional resection toward and away from the DNA end, which commits to HR.

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