ATM phosphorylates the FATC domain of DNA-PKcs at threonine 4102 to promote non-homologous end joining.

Autor:	Lu H; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX75390, USA., Zhang Q; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX75390, USA., Laverty DJ; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA02115, USA., Puncheon AC; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX75390, USA., Augustine MM; Division of Surgical Oncology, Department of Surgery, UT Southwestern Medical Center, Dallas, TX75390, USA.; Department of Surgery, North Texas VA Medical Center, Dallas, TX75216, USA., Williams GJ; Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Nagel ZD; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA02115, USA., Chen BPC; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX75390, USA., Davis AJ; Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX75390, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2023 Jul 21; Vol. 51 (13), pp. 6770-6783.
DOI:	10.1093/nar/gkad505
Abstrakt:	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-stranded 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-PKcs), a core NHEJ factor, at its extreme C-terminus at threonine 4102 (T4102) in response to DSBs. Ablating phosphorylation at T4102 attenuates DNA-PKcs kinase activity and this destabilizes the interaction between DNA-PKcs and the Ku-DNA complex, resulting in decreased assembly and stabilization of the NHEJ machinery at DSBs. Phosphorylation at T4102 promotes NHEJ, radioresistance, and increases genomic stability following DSB induction. Collectively, these findings establish a key role for ATM in NHEJ-dependent repair of DSBs through positive regulation of DNA-PKcs. (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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