The MRE11-RAD50-NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

• Published in: Annual review of biochemistry 2018-06, Vol.87 (1), p.263-294
• Main Authors: Syed, Aleem, Tainer, John A
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; ATPase; BRCA1 C-terminal domains; BRCT domains; Breakage; Cancer; coiled-coil domain; Conductors; CtBP-interacting protein tetramerization; CtIP tetramerization; Damage; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA Damage; DNA Repair; DNA Repair Enzymes - chemistry; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; DNA Replication; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; FHA domain; forkhead-associated domain; Genetic recombination; Genomic instability; Homology; Humans; Immunity, Innate; Kinases; Meiosis; Models, Biological; Models, Molecular; MRE11 Homologue Protein - chemistry; MRE11 Homologue Protein - genetics; MRE11 Homologue Protein - metabolism; MRE11 protein; Nijmegen breakage syndrome; Nijmegen breakage syndrome protein 1; nuclease; Precision medicine; Protein A; Proteins; Recombination; Replication; Replication forks; Replication protein A; Ribonucleases; Scaffolding; Signal Transduction; Stability; Telomere - metabolism; Telomeres
• ISSN: 0066-4154; 1545-4509
• DOI: 10.1146/annurev-biochem-062917-012415

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.