| RAD50 is a structural maintenance of chromosomes (SMC)–related ATPase that forms, together with MRE11 and NBS1, the MRN complex, which is a central sensor, processor, and signaling platform for DNA double‑strand breaks, homologous recombination repair, and telomere maintenance. The protein contains Walker A and B ATPase motifs in N‑ and C‑terminal globular domains that come together to form a head domain, connected by long antiparallel coiled coils that dimerize via a conserved Cys–His–Cys–His “zinc hook,” creating a flexible rod that can bridge and tether DNA ends and bring multiple DNA segments into proximity. Within the MRN complex, RAD50 binds DNA ends and uses ATP binding and hydrolysis to allosterically control MRE11 nuclease access to DNA: ATP-bound RAD50 promotes a closed conformation that juxtaposes DNA ends and positions them at the MRE11 active site, whereas ATP hydrolysis relaxes this configuration and modulates progression from end tethering to end resection and subsequent repair steps. MRN uses MRE11 3'–5' exonuclease and endonuclease activities, regulated by RAD50’s ATPase-driven conformational changes, to initiate end resection and generate single-stranded DNA that is then coated by RPA and engaged by RAD51 and other recombination factors, linking RAD50-dependent DNA end control to homologous recombination and single-strand annealing pathways. The MRN complex also functions as an apical DNA damage sensor in checkpoint signaling: RAD50-dependent DNA end tethering and MRN recruitment to break sites are required for efficient activation of ATM and ATR kinases, which phosphorylate multiple downstream targets to enforce cell-cycle arrest, coordinate repair, and influence apoptosis decisions after DNA damage. At telomeres, MRN contributes to t‑loop metabolism and telomere integrity, where RAD50’s DNA-bridging capacity participates in the controlled recognition of telomeric ends while preventing inappropriate activation of DNA damage responses at chromosome termini. RAD50 is highly conserved from archaea to mammals, and human RAD50 deficiency due to biallelic mutations results in Nijmegen breakage syndrome–like disorder with microcephaly, growth retardation, chromosomal instability, and radio-sensitivity, reflecting the central role of RAD50-containing MRN complexes in genome surveillance, DSB repair, and maintaining chromosomal stability in proliferating and differentiating cells. |
