The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis

Nucleic Acids Research
Peter BurkovicsLumir Krejci

Abstract

Successful and accurate completion of the replication of damage-containing DNA requires mainly recombination and RAD18-dependent DNA damage tolerance pathways. RAD18 governs at least two distinct mechanisms: translesion synthesis (TLS) and template switching (TS)-dependent pathways. Whereas TS is mainly error-free, TLS can work in an error-prone manner and, as such, the regulation of these pathways requires tight control to prevent DNA errors and potentially oncogenic transformation and tumorigenesis. In humans, the PCNA-associated recombination inhibitor (PARI) protein has recently been shown to inhibit homologous recombination (HR) events. Here, we describe a biochemical mechanism in which PARI functions as an HR regulator after replication fork stalling and during double-strand break repair. In our reconstituted biochemical system, we show that PARI inhibits DNA repair synthesis during recombination events in a PCNA interaction-dependent way but independently of its UvrD-like helicase domain. In accordance, we demonstrate that PARI inhibits HR in vivo, and its knockdown suppresses the UV sensitivity of RAD18-depleted cells. Our data reveal a novel human regulatory mechanism that limits the extent of HR and represents a new p...Continue Reading

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Citations

Mar 23, 2017·Critical Reviews in Biochemistry and Molecular Biology·Dana Branzei, Barnabas Szakal
Feb 18, 2017·Genes·Yanzhe GaoYang Yang
Sep 13, 2017·Molecular and Cellular Biology·Ayako L MochizukiShinichiro Chuma
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May 7, 2020·Genes·Eric Huselid, Samuel F Bunting
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Dec 28, 2018·Genes·Wendy LeungAnja-Katrin Bielinsky
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Dec 8, 2020·Therapeutic Advances in Medical Oncology·Bo ChenHailin Tang
Feb 6, 2017·Molecular Cell·Katherine N Choe, George-Lucian Moldovan

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