Journal
ANNUAL REVIEW OF BIOCHEMISTRY, VOL 87
Volume 87, Issue -, Pages 263-294Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-biochem-062917-012415
Keywords
ATPase; nuclease; FHA domain; forkhead-associated domain; BRCT domains; BRCA1 C-terminal domains; coiled-coil domain; CtIP tetramerization; CtBP-interacting protein tetramerization
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Funding
- NCI NIH HHS [R01 CA200231, P01 CA092584, R01 CA117638] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA200231, P01CA092584, R01CA117638] Funding Source: NIH RePORTER
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Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette-ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11-RAD50-NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. MRN can interfere with cancer therapy and is an attractive target for precision medicine. Its conformations change the paradigm whereby kinases initiate damage sensing. Delineated results reveal kinase activation, posttranslational targeting, functional scaffolding, conformations storing binding energy and enabling access, interactions with hub proteins such as replication protein A (RPA), and distinct networks at DNA breaks and forks. MRN biochemistry provides prototypic insights into how it initiates, implements, and regulates multifunctional responses to genomic stress.
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