title: Competition between NBS1 and ATMIN controls ATM signaling pathway choice.
abstract: Ataxia telangiectasia mutated (ATM) protein kinase activation by DNA double-strand breaks (DSBs) requires the Mre11-Rad50-NBS1 (MRN) complex, whereas ATM interactor (ATMIN) protein is required for ATM signaling induced by changes in chromatin structure. We show here that NBS1 and ATMIN proteins compete for ATM binding and that this mechanism controls ATM function. DSB-induced ATM substrate phosphorylation was increased in atmin mutant cells. Conversely, NBS1 deficiency resulted in increased ATMIN-dependent ATM signaling. Thus, the absence of one cofactor increased flux through the alternative pathway. Notably, ATMIN deficiency rescued the cellular lethality of NBS1-deficient cells, and NBS1/ATMIN double deficiency resulted in complete abrogation of ATM signaling and profound radiosensitivity. Hence, ATMIN and NBS1 mediate all ATM signaling by DSBs, and increased ATMIN-dependent ATM signaling explains the different phenotypes of nbs1- and atm-mutant cells. Thus, the antagonism and redundancy of ATMIN and NBS1 constitute a crucial regulatory mechanism for ATM signaling and function.
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK, London Research Institute, London, UK.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Zhang
authors.forename: Kay
authors.initials: K
authors.lastname: Penicud
authors.forename: Christopher
authors.initials: C
authors.lastname: Bruhn
authors.forename: Joanna I
authors.initials: JI
authors.lastname: Loizou
authors.forename: Nnennaya
authors.initials: N
authors.lastname: Kanu
authors.forename: Zhao-Qi
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C554480:ATMIN protein, mouse; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases