NYMC Faculty Publications
First Page
3176
Last Page
3189
Document Type
Article
Publication Date
4-20-2016
Department
Biochemistry and Molecular Biology
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.
Recommended Citation
Burkovics, P., Dome, L., Juhasz, S., Altmannova, V., Sebesta, M., Pacesa, M., et al. (2016). The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis. Nucleic Acids Research, 44(7), 3176-3189. doi: 10.1093/nar/gkw024
Publisher's Statement
Originally published in Nucleic Acids Research. Licensed under CC-BY 4.0. https://doi.org/10.1093/nar/gkw024