The ZNF365 locus is associated with breast cancer risk in carriers of mutated BRCA1 and BRCA2, which are important molecules required for DNA damage response. Previously, we demonstrated that ZNF365 is necessary for timely resolution of replication intermediates of genomic fragile sites and, thus, for suppression of genomic instability; however, the mechanism underlying the function of ZNF365 on damaged DNA and stalled replication forks remains unknown. Here, we demonstrate that ZNF365 is induced by DNA double-strand break (DSB) signals, is involved in the homologous recombination (HR) repair pathway, and maintains genome integrity during DNA replication. On the mechanistic level, ZNF365 interacts with poly(ADP-ribose) polymerase (PARP) 1 to tether MRE11 to the DNA end resection site. Loss of ZNF365 results in delayed mitotic progression and exit due to increased replication stress, ultimately leading to cytokinesis failure, re-duplication of centrosomes, and increased aneuploidy. Collectively, these results suggest an HR repair-dependent function of ZNF365 in preventing genomic instability.
