title: UBR5-mediated ubiquitination of ATMIN is required for ionizing radiation-induced ATM signaling and function.
abstract: The Mre11/Rad50/NBS1 (MRN) protein complex and ATMIN protein mediate ATM kinase signaling in response to ionizing radiation (IR) and chromatin changes, respectively. NBS1 and ATMIN directly compete for ATM binding, but the molecular mechanism favoring either NBS1 or ATMIN in response to specific stimuli is enigmatic. Here, we identify the E3 ubiquitin ligase UBR5 as a key component of ATM activation in response to IR. UBR5 interacts with ATMIN and catalyzes ubiquitination of ATMIN at lysine 238 in an IR-stimulated manner, which decreases ATMIN interaction with ATM and promotes MRN-mediated signaling. We show that UBR5 deficiency, or mutation of ATMIN lysine 238, prevents ATMIN dissociation from ATM and inhibits ATM and NBS1 foci formation after IR, thereby impairing checkpoint activation and increasing radiosensitivity. Thus, UBR5-mediated ATMIN ubiquitination is a vital event for ATM pathway selection and activation in response to DNA damage.
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
authors.forename: Tianyi
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
authors.forename: Janet
authors.initials: J
authors.lastname: Cronshaw
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;
authors.forename: Nnennaya
authors.initials: N
authors.lastname: Kanu
authors.affiliation: Protein Analysis and Proteomics Laboratory, Clare Hall Laboratories, Cancer Research UK London Research Institute, South Mimms EN6 3LD, Hertfordshire, United Kingdom; and.
authors.forename: Ambrosius P
authors.initials: AP
authors.lastname: Snijders
authors.affiliation: Mammalian Genetics Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, United Kingdom;School of Medicine, Guy's Campus, King's College London, London SE1 1UL, United Kingdom axel.behrens@cancer.org.uk.
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D008239:Lysine / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects*; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: C554480:ATMIN protein, mouse; D002352:Carrier Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C489244:UBR5 protein, mouse; D044767:Ubiquitin-Protein Ligases; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D008239:Lysine
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