Abstract
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.
Highlights
Reduced BRCA1 expression causes homologous recombination (HR) repair defects in highgrade serous ovarian cancers (HGSOCs)
We show that BRCA1 transcription is regulated by ZC3H18, which we demonstrate has a previously unknown biochemical function: ZC3H18 is a DNA-binding protein that interacts with an E2F site in the BRCA1 promoter and that activates transcripton
This study shows that ZC3H18 binding to an E2F site in the BRCA1 promoter enhances the association of E2F4 with an adjacent E2F site to activate BRCA1 transcription
Summary
Reduced BRCA1 expression causes homologous recombination (HR) repair defects in highgrade serous ovarian cancers (HGSOCs). In ZC3H18 siRNA-transfected ovarian cancer cells, we found no evidence of alternative BRCA1 RNA splicing using a PCR-based method[25] (Supplementary Fig. 5a). As previously reported[28], bisulfite sequencing revealed that 10–20% of the BRCA1 promoter CpG sites were methylated in control siRNA-transfected OVCAR-8 cells (Fig. 3a).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
