title: Disease-associated MRE11 mutants impact ATM/ATR DNA damage signaling by distinct mechanisms.
abstract: DNA double-strand breaks (DSBs) can lead to instability of the genome if not repaired correctly. The MRE11/RAD50/NBS1 (MRN) complex binds DSBs and initiates damage-induced signaling cascades via activation of the ataxia-telangiectasia mutated (ATM) and ataxia-telangiectasia- and rad3-related (ATR) kinases. Mutations throughout MRE11 cause ataxia-telangiectasia-like disorder (ATLD) featuring cerebellar degeneration, and cancer-predisposition in certain kindreds. Here, we have examined the impact on DNA damage signaling of several disease-associated MRE11A alleles to gain greater understanding of the mechanisms underlying the diverse disease sequelae of ATLD. To this end, we have designed a system whereby endogenous wild-type Mre11a is conditionally deleted and disease-associated MRE11 mutants are stably expressed at physiologic levels. We find that mutations in the highly conserved N-terminal domain impact ATM signaling by perturbing both MRE11 interaction with NBS1 and MRE11 homodimerization. In contrast, an inherited allele in the MRE11 C-terminus maintains MRN interactions and ATM/ATR kinase activation. These findings reveal that ATLD patients have reduced ATM activation resulting from at least two distinct mechanisms: (i) N-terminal mutations destabilize MRN interactions, and (ii) mutation of the extreme C-terminus maintains interactions but leads to low levels of the complex. The N-terminal mutations were found in ATLD patients with childhood cancer; thus, our studies suggest a clinically relevant dichotomy in MRE11A alleles. More broadly, these studies underscore the importance of understanding specific effects of hypomorphic disease-associated mutations to achieve accurate prognosis and appropriate long-term medical surveillance.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Regal
authors.forename: Todd A
authors.initials: TA
authors.lastname: Festerling
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Buis
authors.forename: David O
authors.initials: DO
authors.lastname: Ferguson
mesh_terms: D000483:Alleles; D001260:Ataxia Telangiectasia / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D006801:Humans; D000076228:MRE11 Homologue Protein; D009154:Mutation; D009369:Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; D000076228:MRE11 Homologue Protein
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