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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities
Molecular Cell, Volume 53, No. 1, Year 2014
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Description
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 nonhomologous 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. © 2014 Elsevier Inc.
Authors & Co-Authors
Shibata, Atsushi K.
United Kingdom, Brighton
University of Sussex
Japan, Maebashi
Gunma University
Harding, Shane M.
Canada, Toronto
University of Toronto
Genois, Marie Michelle
Canada, Quebec
Université Laval
Ismail, A. M.
United Kingdom, Brighton
University of Sussex
Bristow, Robert G.
Canada, Toronto
University of Toronto
Masson, Jean Yves
Canada, Quebec
Université Laval
Jeggo, Penny A.
United Kingdom, Brighton
University of Sussex
Tainer, John A.
United States, San Diego
Scripps Research Institute
United States, Berkeley
Lawrence Berkeley National Laboratory
Statistics
Citations: 402
Authors: 8
Affiliations: 9
Identifiers
Doi:
10.1016/j.molcel.2013.11.003
ISSN:
10974164
Research Areas
Cancer
Genetics And Genomics