Cleavage of the BRCT tandem domains of nibrin by the 657del5 mutation affects the DNA damage response less than the Arg215Trp mutation

摘要: The Nijmegen breakage syndrome (NBS) is a genetic disorder caused by mutations in NBN gene and characterized chromosomal instability hypersensitivity to ionizing radiations (IR). N-terminus of nibrin (NBN) contains tandem breast cancer 1 (BRCA1) carboxy-terminal (BRCT) domain that represents one the major mediators phosphorylation-dependent protein-protein interactions processes related cell cycle checkpoint DNA repair functions. Patients with NBS compound heterozygous for 657del5 hypomorphic mutation Arg215Trp missense (corresponding 643C>T mutation) display clinical phenotype more severe than patients homozygous mutation. Here, we show both mutations, occurring within BRCT domains NBN, although not altering assembly MRE11/RAD50/NBN (MRN) complex, affect MRE11 IR-induced nuclear foci (IRIF) formation double-strand break (DSB) signaling via phosphorylation ataxia-telangiectasia-mutated (ATM) kinase ATM downstream targets (e.g., SMC1 p53). Remarkably, data obtained indicate cleavage affects damage response less Indeed, 70-kDa fragment, arising from mutation, maintains capability interact γ-H2AX form IRIF. Altogether, role localization MRN complex at DSB activation highlighted.