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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.

SUBMITTER: Zhang T 

PROVIDER: S-EPMC4143036 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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UBR5-mediated ubiquitination of ATMIN is required for ionizing radiation-induced ATM signaling and function.

Zhang Tianyi T   Cronshaw Janet J   Kanu Nnennaya N   Snijders Ambrosius P AP   Behrens Axel A  

Proceedings of the National Academy of Sciences of the United States of America 20140804 33


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  ...[more]

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