DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities. Shibata, A., Moiani, D., Arvai, A. S., Perry, J., Harding, S. M., Genois, M., Maity, R., van Rossum-Fikkert, S., Kertokalio, A., Romoli, F., Ismail, A., Ismalaj, E., Petricci, E., Neale, M. J., Bristow, R. G., Masson, J., Wyman, C., Jeggo, P. A., & Tainer, J. A. Molecular Cell, 53(1):7–18, January, 2014. doi abstract bibtex 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.
@article{shibata_dna_2014-1,
title = {{DNA} double-strand break repair pathway choice is directed by distinct {MRE11} nuclease activities},
volume = {53},
issn = {1097-4164},
doi = {10.1016/j.molcel.2013.11.003},
abstract = {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.},
language = {eng},
number = {1},
journal = {Molecular Cell},
author = {Shibata, Atsushi and Moiani, Davide and Arvai, Andrew S. and Perry, Jefferson and Harding, Shane M. and Genois, Marie-Michelle and Maity, Ranjan and van Rossum-Fikkert, Sari and Kertokalio, Aryandi and Romoli, Filippo and Ismail, Amani and Ismalaj, Ermal and Petricci, Elena and Neale, Matthew J. and Bristow, Robert G. and Masson, Jean-Yves and Wyman, Claire and Jeggo, Penny A. and Tainer, John A.},
month = jan,
year = {2014},
keywords = {Cell Line, Chromatin, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Repair Enzymes, DNA-Binding Proteins, Enzyme Inhibitors, Exodeoxyribonucleases, G2 Phase, Gamma Rays, Humans, Recombinational DNA Repair, Replication Protein A},
pages = {7--18},
}
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A."],"bibdata":{"bibtype":"article","type":"article","title":"DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities","volume":"53","issn":"1097-4164","doi":"10.1016/j.molcel.2013.11.003","abstract":"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.","language":"eng","number":"1","journal":"Molecular Cell","author":[{"propositions":[],"lastnames":["Shibata"],"firstnames":["Atsushi"],"suffixes":[]},{"propositions":[],"lastnames":["Moiani"],"firstnames":["Davide"],"suffixes":[]},{"propositions":[],"lastnames":["Arvai"],"firstnames":["Andrew","S."],"suffixes":[]},{"propositions":[],"lastnames":["Perry"],"firstnames":["Jefferson"],"suffixes":[]},{"propositions":[],"lastnames":["Harding"],"firstnames":["Shane","M."],"suffixes":[]},{"propositions":[],"lastnames":["Genois"],"firstnames":["Marie-Michelle"],"suffixes":[]},{"propositions":[],"lastnames":["Maity"],"firstnames":["Ranjan"],"suffixes":[]},{"propositions":["van"],"lastnames":["Rossum-Fikkert"],"firstnames":["Sari"],"suffixes":[]},{"propositions":[],"lastnames":["Kertokalio"],"firstnames":["Aryandi"],"suffixes":[]},{"propositions":[],"lastnames":["Romoli"],"firstnames":["Filippo"],"suffixes":[]},{"propositions":[],"lastnames":["Ismail"],"firstnames":["Amani"],"suffixes":[]},{"propositions":[],"lastnames":["Ismalaj"],"firstnames":["Ermal"],"suffixes":[]},{"propositions":[],"lastnames":["Petricci"],"firstnames":["Elena"],"suffixes":[]},{"propositions":[],"lastnames":["Neale"],"firstnames":["Matthew","J."],"suffixes":[]},{"propositions":[],"lastnames":["Bristow"],"firstnames":["Robert","G."],"suffixes":[]},{"propositions":[],"lastnames":["Masson"],"firstnames":["Jean-Yves"],"suffixes":[]},{"propositions":[],"lastnames":["Wyman"],"firstnames":["Claire"],"suffixes":[]},{"propositions":[],"lastnames":["Jeggo"],"firstnames":["Penny","A."],"suffixes":[]},{"propositions":[],"lastnames":["Tainer"],"firstnames":["John","A."],"suffixes":[]}],"month":"January","year":"2014","keywords":"Cell Line, Chromatin, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Repair Enzymes, DNA-Binding Proteins, Enzyme Inhibitors, Exodeoxyribonucleases, G2 Phase, Gamma Rays, Humans, Recombinational DNA Repair, Replication Protein A","pages":"7–18","bibtex":"@article{shibata_dna_2014-1,\n\ttitle = {{DNA} double-strand break repair pathway choice is directed by distinct {MRE11} nuclease activities},\n\tvolume = {53},\n\tissn = {1097-4164},\n\tdoi = {10.1016/j.molcel.2013.11.003},\n\tabstract = {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.},\n\tlanguage = {eng},\n\tnumber = {1},\n\tjournal = {Molecular Cell},\n\tauthor = {Shibata, Atsushi and Moiani, Davide and Arvai, Andrew S. and Perry, Jefferson and Harding, Shane M. and Genois, Marie-Michelle and Maity, Ranjan and van Rossum-Fikkert, Sari and Kertokalio, Aryandi and Romoli, Filippo and Ismail, Amani and Ismalaj, Ermal and Petricci, Elena and Neale, Matthew J. and Bristow, Robert G. and Masson, Jean-Yves and Wyman, Claire and Jeggo, Penny A. and Tainer, John A.},\n\tmonth = jan,\n\tyear = {2014},\n\tkeywords = {Cell Line, Chromatin, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Repair Enzymes, DNA-Binding Proteins, Enzyme Inhibitors, Exodeoxyribonucleases, G2 Phase, Gamma Rays, Humans, Recombinational DNA Repair, Replication Protein A},\n\tpages = {7--18},\n}\n\n","author_short":["Shibata, A.","Moiani, D.","Arvai, A. 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