title: The Mre11-Nbs1 Interface Is Essential for Viability and Tumor Suppression.
abstract: The Mre11 complex (Mre11, Rad50, and Nbs1) is integral to both DNA repair and ataxia telangiectasia mutated (ATM)-dependent DNA damage signaling. All three Mre11 complex components are essential for viability at the cellular and organismal levels. To delineate essential and non-essential Mre11 complex functions that are mediated by Nbs1, we used TALEN-based genome editing to derive Nbs1 mutant mice (Nbs1midmice), which harbor mutations in the Mre11 interaction domain of Nbs1. Nbs1midalleles that abolished interaction were incompatible with viability. Conversely, a 108-amino-acid Nbs1 fragment comprising the Mre11 interface was sufficient to rescue viability and ATM activation in cultured cells and support differentiation of hematopoietic cells in vivo. These data indicate that the essential role of Nbs1 is via its interaction with Mre11 and that most of the Nbs1 protein is dispensable for Mre11 complex functions and suggest that Mre11 and Rad50 directly activate ATM.
authors.affiliation: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Jun Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center, 3000 Rotterdam, the Netherlands; Department of Radiation Oncology, Erasmus University Medical Center, 3000 Rotterdam, the Netherlands.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Grosbart
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Roopesh
authors.initials: R
authors.lastname: Anand
authors.affiliation: Department of Molecular Genetics, Erasmus University Medical Center, 3000 Rotterdam, the Netherlands; Department of Radiation Oncology, Erasmus University Medical Center, 3000 Rotterdam, the Netherlands.
authors.forename: Claire
authors.initials: C
authors.lastname: Wyman
authors.affiliation: Institute for Research in Biomedicine, Università della Svizzera Italiana, Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.
authors.forename: Petr
authors.initials: P
authors.lastname: Cejka
authors.affiliation: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. Electronic address: petrinij@mskcc.org.
authors.forename: John H J
authors.initials: JHJ
authors.lastname: Petrini
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D002470:Cell Survival; D017124:Conserved Sequence; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins; D047108:Embryonic Development; D019143:Evolution, Molecular; D005333:Fetus / Q000166:cytology; D006410:Hematopoiesis; D008099:Liver / Q000196:embryology; D000076228:MRE11 Homologue Protein / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D000076228:MRE11 Homologue Protein
keywords: ATM activation; Mre11 complex assembly; Mre11-Nbs1 interface; Nbs1(mid) mutants