Bennett, L.G., Wilkie, A.M., Antonopoulou, E. et al. (8 more authors) (2020) MRNIP is a replication fork protection factor. Science Advances, 6 (28). eaba5974. ISSN 2375-2548
Abstract
The remodeling of stalled replication forks to form four-way DNA junctions is an important component of the replication stress response. Nascent DNA at the regressed arms of these reversed forks is protected by RAD51 and the tumor suppressors BRCA1/2, and when this function is compromised, stalled forks undergo pathological MRE11-dependent degradation, leading to chromosomal instability. However, the mechanisms regulating MRE11 functions at reversed forks are currently unclear. Here, we identify the MRE11-binding protein MRNIP as a novel fork protection factor that directly binds to MRE11 and specifically represses its exonuclease activity. The loss of MRNIP results in impaired replication fork progression, MRE11 exonuclease–dependent degradation of reversed forks, persistence of underreplicated genomic regions, chemosensitivity, and chromosome instability. Our findings identify MRNIP as a novel regulator of MRE11 at reversed forks and provide evidence that regulation of specific MRE11 nuclease activities ensures protection of nascent DNA and thereby genome integrity.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). (http://creativecommons.org/licenses/by-nc/4.0/) |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) |
Funding Information: | Funder Grant number YORKSHIRE CANCER RESEARCH S406SC |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 14 Jul 2020 13:31 |
Last Modified: | 14 Jul 2020 13:31 |
Status: | Published |
Publisher: | American Association for the Advancement of Science (AAAS) |
Refereed: | Yes |
Identification Number: | 10.1126/sciadv.aba5974 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:163246 |