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

Peter Burkovics, Lili Dome, Szilvia Juhasz, Veronika Altmannova, Marek Sebesta, Martin Pacesa, Kasper Fugger, Claus Storgaard Sorensen, Marietta Y.W.T. Lee, Lajos Haracska, Lumir Krejci

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19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3176-3189
Number of pages14
JournalNucleic acids research
Volume44
Issue number7
DOIs
Publication statusPublished - Jan 20 2016

ASJC Scopus subject areas

  • Genetics

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    Burkovics, P., Dome, L., Juhasz, S., Altmannova, V., Sebesta, M., Pacesa, M., Fugger, K., Sorensen, C. S., Lee, M. Y. W. T., Haracska, L., & Krejci, L. (2016). The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis. Nucleic acids research, 44(7), 3176-3189. https://doi.org/10.1093/nar/gkw024