The PCNA-associated protein PARI negatively regulates homologous recombination via the inhibition of DNA repair synthesis
| Authors | |
|---|---|
| Year of publication | 2016 |
| Type | Article in Periodical |
| Magazine / Source | Nucleic Acids Research |
| MU Faculty or unit | |
| Citation | |
| Doi | http://dx.doi.org/10.1093/nar/gkw024 |
| Field | Genetics and molecular biology |
| Keywords | CELL NUCLEAR ANTIGEN; UBIQUITIN-BINDING DOMAINS; DAMAGE TOLERANCE PATHWAY; BLOOMS-SYNDROME HELICASE; SACCHAROMYCES-CEREVISIAE; REPLICATION FORK; POSTREPLICATION REPAIR; TRANSLESION SYNTHESIS; GENOMIC STABILITY; SUMO MODIFICATION |
| Description | 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. |
| Related projects: |