PTIP UFMylation promotes replication fork degradation in BRCA1-deficient cells

Abstract

“BRCAness” defines cancers that are homologous recombination (HR)-deficient due to BRCA1 or BRCA2 mutations. These mutations confer synthetic lethality with PARP1/2 inhibitors. The chromatin regulator PTIP promotes stalled replication fork degradation in “BRCAness” 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 PARP 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.