ATM phosphorylates the FATC domain of DNA-PK cs at threonine 4102 to promote non-homologous end joining.
bioRxiv
; 2023 Feb 02.
Article
em En
| MEDLINE
| ID: mdl-36778257
ABSTRACT
Ataxia-telangiectasia mutated (ATM) drives the DNA damage response via modulation of multiple signal transduction and DNA repair pathways. Previously, ATM activity was implicated in promoting the non-homologous end joining (NHEJ) pathway to repair a subset of DNA double strand breaks (DSBs), but how ATM performs this function is still unclear. In this study, we identified that ATM phosphorylates the DNA-dependent protein kinase catalytic subunit (DNA-PK cs ), a core NHEJ factor, at its extreme C-terminus at threonine 4102 (T4102) in response to DSBs. Phosphorylation at T4102 stabilizes the interaction between DNA-PK cs and the Ku-DNA complex and promotes assembly and stabilization of the NHEJ machinery at DSBs. Ablating phosphorylation at this site results in decreased NHEJ, radiosensitivity, and increased radiation-induced genomic instability. Collectively, these findings establish a key role for ATM in NHEJ-dependent repair of DSBs through positive regulation of DNA-PK cs .
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1
Base de dados:
MEDLINE
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
BioRxiv
Ano de publicação:
2023
Tipo de documento:
Article