Journal
MOLECULAR CELL
Volume 53, Issue 1, Pages 7-18Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2013.11.003
Keywords
-
Categories
Funding
- National Institutes of Health [CA117638]
- National Cancer Institute [P01 CA092584]
- Netherlands Organization for Scientific Research [VICI 700.56.441]
- U.S. Department of Energy program Integrated Diffraction Analysis Technologies (IDAT)
- CIHR
- Medical Research Council
- Association for International Cancer Research
- Department of Health
- Wellcome Trust
- NATIONAL CANCER INSTITUTE [P01CA092584, R01CA117638] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM105404] Funding Source: NIH RePORTER
- Medical Research Council [G0800005] Funding Source: researchfish
- MRC [G0800005] Funding Source: UKRI
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available