Mre11–Rad50–Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin templateThis paper is one of a selection of papers published in this Special Issue, entitled 28th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.
Abstract
The Mre11–Rad50–Nbs1 (MRN) complex is providing paradigm-shifting results of exceptional biomedical interest. MRN is among the earliest respondents to DNA double-strand breaks (DSBs), and MRN mutations cause the human cancer predisposition diseases Nijmegen breakage syndrome and ataxia telangiectasia-like disorder (ATLD). MRN’s 3-protein multidomain composition promotes its central architectural, structural, enzymatic, sensing, and signaling functions in DSB responses. To organize the MRN complex, the Mre11 exonuclease directly binds Nbs1, DNA, and Rad50. Rad50, a structural maintenance of chromosome (SMC) related protein, employs its ATP-binding cassette (ABC) ATPase, Zn hook, and coiled coils to bridge DSBs and facilitate DNA end processing by Mre11. Contributing to MRN regulatory roles, Nbs1 harbors N-terminal phosphopeptide interacting FHA and BRCT domains, as well as C-terminal ataxia telangiectasia mutated (ATM) kinase and Mre11 interaction domains. Current emerging structural and biological evidence suggests that MRN has 3 coupled critical roles in DSB sensing, stabilization, signaling, and effector scaffolding: (1) expeditious establishment of protein – nucleic acid tethering scaffolds for the recognition and stabilization of DSBs; (2) initiation of DSB sensing, cell-cycle checkpoint signaling cascades, and establishment of epigenetic marks via the ATM kinase; and (3) functional regulation of chromatin remodeling in the vicinity of a DSB.
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The MRN complex is needed to activate ATM-dependent DDR after double-strand breaks and ATR-dependent DDR after stalled replication forks.
“The MRN complex is required for the activation of ATM and ATR-dependent DDR pathways in response to DSBs and stalled DNA replication forks, respectively [57, 125, 218].”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [218]
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- Authors
- Williams, R. S., Williams, J. S., & Tainer, J. A.
- Affiliations
- Scripps Research Institute (US)
- Venue
- Biochemistry and Cell Biology
- Publisher
- Canadian Science Publishing
- Published
- 2007-08
- Volume
- 85
- Issue
- 4
- Pages
- 509-520
- ISSN
- 0829-8211 (ISSN-L)
- 1208-6002
- OpenAlex
- W2161560609
- Cited by
- 399
- References
- 119
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 7 · 2023: 10 · 2022: 8 · 2021: 13 · 2020: 17 · 2019: 15 · 2018: 22 · 2017: 22 · 2016: 18 · 2015: 19 · 2014: 27 · 2013: 24 · 2012: 27
- FWCI
- 3.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biochemistry and Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA92584, CA117638, R01CA117638, P01CA092584)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- Mre11-Rad50-Nbs1 complex, MRN complex, DNA double-strand break repair, Nijmegen breakage syndrome, ataxia-telangiectasia-like disorder, RAD50, NBS1, ATM kinase, DNA end processing, chromatin remodeling, epigenetic modifications
- MeSH terms
- MRE11 Homologue Protein, Chromatin, DNA, DNA Repair, DNA-Binding Proteins, Enzyme Activation, Humans, Models, Molecular, Nuclear Proteins, Protein Conformation, Signal Transduction, Protein Serine-Threonine Kinases, Acid Anhydride Hydrolases, Cell Cycle Proteins, Tumor Suppressor Proteins, DNA Repair Enzymes, Macromolecular Substances, DNA Breaks, Double-Stranded, Ataxia Telangiectasia Mutated Proteins
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