Mre11Rad50Nbs1

Mre11-Rad50-Nbs1, commonly known as the MRN complex, is a highly conserved protein assembly that functions as a primary sensor and mediator of DNA double-strand break repair in eukaryotes and some archaea. In humans, the complex comprises MRE11, RAD50, and NBS1 (also called NBN). It coordinates detection of DNA damage, processing of broken ends, and initiation of signaling pathways essential for maintaining genome stability.

MRE11 is a dimeric nuclease with both 3'-to-5' exonuclease and endonuclease activities, contributing to the initial processing of DNA ends. RAD50 is an ATPase with long coiled-coil domains that can tether DNA ends and undergo ATP-driven conformational changes to bridge breaks. NBS1 functions as the regulatory adaptor, guiding the complex to damage sites and facilitating recruitment of downstream factors. The three components work together to position DNA ends for repair and to regulate the subsequent signaling events.

Functionally, the MRN complex binds to DNA double-strand breaks, promotes end resection to generate 3' single-stranded DNA, and collaborates with other proteins to direct repair via homologous recombination or, when appropriate, non-homologous end joining. It also plays a key role in activating the ATM kinase, thereby triggering cell-cycle checkpoints and broader DNA damage responses. Additional roles include telomere maintenance, meiotic recombination, and stabilization of stalled replication forks.

Clinical significance of MRN dysfunction is notable. Germline mutations in MRE11, RAD50, or NBS1 cause disorders such as Nijmegen breakage syndrome, which features growth retardation, immunodeficiency, microcephaly, and cancer predisposition, and Ataxia-telangiectasia–like disorder. MRN defects heighten cellular sensitivity to ionizing radiation and impair DNA damage signaling, contributing to genome instability and disease risk.