The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities
Open accessAbstract
SUMMARY 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 DSB repair 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. Whilst endo- or exonuclease inhibition impairs radiation-induced RPA chromatin binding, suggesting diminished resection, the inhibitors surprisingly direct different repair outcomes. Endonuclease inhibition promotes NHEJ in lieu of HR, whilst 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 exo and EXO1/BLM bidirectional resection towards and away from the DNA end, which commits to HR.
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Cites
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Metadata
- Authors
- Shibata, A., Moiani, D., Arvai, A. S., Perry, J., Harding, S. M., Genois, M.-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.-Y., Wyman, C., Jeggo, P. A., & Tainer, J. A.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 53
- Issue
- 1
- Pages
- 7-18
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2140345256
- Cited by
- 567
- References
- 46
- FWCI
- 17.21
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Shibata, A., Moiani, D., Arvai, A. S., Perry, J., Harding, S. M., Genois, M.-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.-Y., Wyman, C., Jeggo, P. A., & Tainer, J. A. (2014). DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities. Molecular Cell. https://doi.org/10.1016/j.molcel.2013.11.003
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
