p53 coordinates base excision repair to prevent genomic instability

Nucleic Acids Research
Mattia PolettoG L Dianov

Abstract

DNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these processes are extremely well-coordinated as unrepaired DNA single strand breaks (SSBs) can be converted to DNA double strand breaks during replication thus triggering genomic instability. However, the mechanism(s) governing the BER process are poorly understood. Here we show that accumulation of unrepaired SSBs triggers a p53/Sp1-dependent downregulation of APE1, the endonuclease responsible for the DNA incision during BER. Importantly, we demonstrate that impaired p53 function, a characteristic of many cancers, leads to a failure of the BER coordination mechanism, overexpression of APE1, accumulation of DNA strand breaks and results in genomic instability. Our data provide evidence for a previously unrecognized mechanism for coordination of BER by p53, and its dysfunction in p53-inactivated cells.

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Citations

Jul 7, 2017·Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine·Haiyang YuQiande Liao
Oct 6, 2017·Antioxidants & Redox Signaling·Bryndon J Oleson, John A Corbett
Dec 1, 2017·Human & Experimental Toxicology·Irem Dogan TuracliSelda Demirtas
Sep 6, 2018·International Journal of Cancer. Journal International Du Cancer·Krzysztof SzyfterAlfio Ferlito
Nov 25, 2018·Cellular Microbiology·Nitish GulveThomas Rudel
May 9, 2019·International Journal of Molecular Sciences·Arianna Barchiesi, Carlo Vascotto
May 31, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Panagiotis KarakaidosTheodoros Rampias
Aug 31, 2019·Journal of Applied Genetics·Katarzyna Kiwerska, Krzysztof Szyfter
Dec 15, 2020·Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology·María Fernanda GalíndezMabel Brunotto
Mar 14, 2020·NAR Cancer·Polina S LoshchenovaGrigory L Dianov

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