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Reduced BRCA1 expression causes homologous recombination (HR) repair defects in high-grade serous ovarian cancers (HGSOCs). Here, we demonstrate that  BRCA1  is transcriptionally activated by a previously unknown function of ZC3H18. We show that ZC3H18 is a DNA-binding protein that interacts with an E2F site in the  BRCA1  promoter where it facilitates recruitment of E2F4 to an adjacent E2F site to promote  BRCA1  transcription. Consistent with ZC3H18 role in activating BRCA1 expression, ZC3H18 depletion induces  BRCA1  promoter methylation, reduces BRCA1 expression, disrupts HR, and sensitizes cells to DNA crosslinkers and poly(ADP-ribose) polymerase inhibitors. Moreover, in patient-derived xenografts and primary HGSOC tumors,  ZC3H18  and  E2F4  mRNA levels are positively correlated with  BRCA1  mRNA levels, further supporting ZC3H18 role in regulating  BRCA1 . Given that  ZC3H18  lies within 16q24.2, a region with frequent copy number loss in HGSOC, these findings suggest that  ZC3H18  copy number losses could contribute to HR defects in HGSOC.

ZC3H18 specifically binds and activates the BRCA1 promoter to facilitate homologous recombination in ovarian cancer