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

Arun Kanakkanthara, Catherine J. Huntoon, Xiaonan Hou, Minzhi Zhang, Ethan P. Heinzen, Daniel R. O’Brien, Ann L. Oberg, S. John Weroha, Scott H. Kaufmann and Larry M. Karnitz ()
Additional contact information
Arun Kanakkanthara: Mayo Clinic
Catherine J. Huntoon: Mayo Clinic
Xiaonan Hou: Mayo Clinic
Minzhi Zhang: Mayo Clinic
Ethan P. Heinzen: Mayo Clinic
Daniel R. O’Brien: Mayo Clinic
Ann L. Oberg: Mayo Clinic
S. John Weroha: Mayo Clinic
Scott H. Kaufmann: Mayo Clinic
Larry M. Karnitz: Mayo Clinic

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-019-12610-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12610-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-12610-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().