REV7-p53 interaction inhibits ATM-mediated DNA damage signaling

ABSTRACT

REV7 is an abundant, multifunctional protein that is a known factor in cell cycle regulation and in several key DNA repair pathways including Trans-Lesion Synthesis (TLS), the Fanconi Anemia (FA) pathway, and DNA Double-Strand Break (DSB) repair pathway choice. Thus far, no direct role has been studied for REV7 in the DNA damage response (DDR) signaling pathway. Here we describe a novel function for REV7 in DSB-induced p53 signaling. We show that REV7 binds directly to p53 to block ATM-dependent p53 Ser15 phosphorylation. We also report that REV7 is involved in the destabilization of p53. These findings affirm REV7’s participation in fundamental cell cycle and DNA repair pathways. Furthermore, they highlight REV7 as a critical factor for the integration of multiple processes that determine viability and genome stability.

KEYWORDS:

• DNA repair
• p53
• ATM
• Fanconi anemia
• DNA double-strand breaks
• MAD2B/

Acknowledgements

We thank Bridget Wilkinson and Justin Clark for assistance with experiments, and Mary Tomida and Luke Tomida for editorial help.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data are presented in the article.

Author contributions

MB and JT conceived and designed the experiments. CV and JT designed the research. MB CB, SK, SN, AT, AS, SA, DD, CV, and JT performed research. MB, KT, SK, SN, AT, SA, DD, CV, and JT analyzed data. DD, CV and JT wrote the paper.

Supporting information

This article contains supporting information.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2024.2333227

Additional information

Funding

This research was supported by National Institutes of Health (NIH) grant 1R15CA263784 (to JT), National Institutes of Health (NIH) grants [R01 ES009558, CA215347, and CA229530 (to CV), SPS KAKENHI Grant 19H04267]; Takeda bioscience Research grant; Mitsubishi Research grant; Naito Research grant; Astellas research foundation (to HS), UNC Charlotte FRG111160 and National Institutes of Health (NIH) grant 1R15CA283775 (as co-I) (to DD).