title: The Rad50 hook domain regulates DNA damage signaling and tumorigenesis.
abstract: The Mre11 complex (Mre11, Rad50, and Nbs1) is a central component of the DNA damage response (DDR), governing both double-strand break repair and DDR signaling. Rad50 contains a highly conserved Zn(2+)-dependent homodimerization interface, the Rad50 hook domain. Mutations that inactivate the hook domain produce a null phenotype. In this study, we analyzed mutants with reduced hook domain function in an effort to stratify hook-dependent Mre11 complex functions. One of these alleles, Rad50(46), conferred reduced Zn(2+) affinity and dimerization efficiency. Homozygous Rad50(46/46) mutations were lethal in mice. However, in the presence of wild-type Rad50, Rad50(46) exerted a dominant gain-of-function phenotype associated with chronic DDR signaling. At the organismal level, Rad50(+/46) exhibited hydrocephalus, liver tumorigenesis, and defects in primitive hematopoietic and gametogenic cells. These outcomes were dependent on ATM, as all phenotypes were mitigated in Rad50(+/46) Atm(+/-) mice. These data reveal that the murine Rad50 hook domain strongly influences Mre11 complex-dependent DDR signaling, tissue homeostasis, and tumorigenesis.
authors.affiliation: Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA;
authors.forename: Ramon
authors.initials: R
authors.lastname: Roset
authors.forename: Akiko
authors.initials: A
authors.lastname: Inagaki
authors.forename: Marcel
authors.initials: M
authors.lastname: Hohl
authors.forename: Fabienne
authors.initials: F
authors.lastname: Brenet
authors.forename: Julien
authors.initials: J
authors.lastname: Lafrance-Vanasse
authors.forename: Julian
authors.initials: J
authors.lastname: Lange
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Scandura
authors.forename: John A
authors.initials: JA
authors.lastname: Tainer
authors.forename: Scott
authors.initials: S
authors.lastname: Keeney
authors.forename: John H J
authors.initials: JH
authors.lastname: Petrini
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005854:Germ Cells / Q000473:pathology; D000076228:MRE11 Homologue Protein; D051379:Mice; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes
keywords: ATM; Mre11 complex; Rad50; double-strand breaks