Phosphorylation of BRCA1 by ATM upon double-strand breaks impacts ATM function in end-resection: A potential feedback loop

Authors

Leilei Qi, Department of Anatomy and Cell Biology, the George Washington University, School of Medicine and Health Sciences, Washington DC20037, USA.
Reka Chakravarthy, Department of Anatomy and Cell Biology, the George Washington University, School of Medicine and Health Sciences, Washington DC20037, USA.
Monica M. Li, Department of Anatomy and Cell Biology, the George Washington University, School of Medicine and Health Sciences, Washington DC20037, USA.
Chu-Xia Deng, Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR China.
Rong Li, Department of Biochemistry and Molecular Medicine, the George Washington University, School of Medicine and Health Sciences, Washington DC20037, USA.
Yanfen Hu, Department of Anatomy and Cell Biology, the George Washington University, School of Medicine and Health Sciences, Washington DC20037, USA.

Document Type

Journal Article

Publication Date

9-16-2022

Journal

iScience

Volume

25

Issue

9

DOI

10.1016/j.isci.2022.104944

Keywords

Biochemistry; Biochemistry applications; Biological sciences

Abstract

BRCA1 maintains genome stability by promoting homologous recombination (HR)-mediated DNA double-strand break (DSB) repair. Mutation of mouse BRCA1-S1152, corresponding to an ATM phosphorylation site in its human counterpart, resulted in increased genomic instability and tumor incidence. In this study, we report that BRCA1-S1152 is part of a feedback loop that sustains ATM activity. BRCA1-S1152A mutation impairs recruitment of the E3 ubiquitin ligase SKP2. This in turn attenuates NBS1-K63 ubiquitination by SKP2 at DSB, impairs sustained ATM activation, and ultimately leads to deficient end resection, the commitment step in the HR repair pathway. Auto-phosphorylation of human ATM at S1981 is known to be important for its kinase activation; we mutated the corresponding amino acid residue in mouse ATM (S1987A) to characterize potential roles of mouse ATM-S1987 in the BRCA1-SKP2-NBS1-ATM feedback loop. Unexpectedly, MEFs carrying the ATM-S1987A knockin mutation maintain damage-induced ATM kinase activation, suggesting a species-specific function of human ATM auto-phosphorylation.

APA Citation

Qi, Leilei; Chakravarthy, Reka; Li, Monica M.; Deng, Chu-Xia; Li, Rong; and Hu, Yanfen, "Phosphorylation of BRCA1 by ATM upon double-strand breaks impacts ATM function in end-resection: A potential feedback loop" (2022). GW Authored Works. Paper 1715.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/1715

Department

Anatomy and Regenerative Biology