Abstract
Homologous-recombination deficiency due to breast cancer 1/2 (BRCA1/2) mutations or mimicking BRCA1/2 mutations confer synthetic lethality with poly-(ADP)-ribose polymerase 1/2 inhibitors. The chromatin regulator Pax2 transactivation domain interacting protein (PTIP) promotes stalled replication fork degradation in BRCA1-deficient cells, but the underlying mechanism by which PTIP regulates stalled replication fork stability is unclear. Here, we performed a series of in vitro analyses to dissect the function of UFMylation in regulating fork stabilization in BRCA1-deficient cells. By denaturing co-immunoprecipitation, we first found that replication stress can induce PTIP UFMylation. Interestingly, this post-translational modification promotes end resection and degradation of nascent DNA at stalled replication forks in BRCA1-deficient cells. By cell viability assay, we found that PTIP-depleted and UFL1-depleted BRCA1 knockdown cells are less sensitive to poly-(ADP)-ribose polymerase inhibitors than the siRNA targeting negative control BRCA1-deficient cells. These results identify a new mechanism by which PTIP UFMylation confers chemoresistance in BRCA1-deficient cells.