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


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 potential target for anticancer therapy.

SUBMITTER: Burkovics P 

PROVIDER: S-EPMC4838361 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Burkovics Peter P   Dome Lili L   Juhasz Szilvia S   Altmannova Veronika V   Sebesta Marek M   Pacesa Martin M   Fugger Kasper K   Sorensen Claus Storgaard CS   Lee Marietta Y W T MY   Haracska Lajos L   Krejci Lumir L  

Nucleic acids research 20160120 7


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 tumorige  ...[more]

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