Downregulation of the cancer susceptibility protein WRAP53β in epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome.

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Abstract

Alterations in the scaffold protein WRAP53β have previously been linked to carcinogenesis and, in particular, associated with an increased risk for epithelial ovarian cancer. Here, we investigated the pathogenic impact and prognostic significance of WRAP53β in connection with epithelial ovarian cancer and examined the underlying mechanisms. We find that reduced expression of WRAP53β in ovarian tumors correlated with attenuated DNA damage response and poor patient survival. Furthermore, in ovarian cancer cell lines, WRAP53β was rapidly recruited to DNA double-strand breaks, where it orchestrated the recruitment of repair factors involved in homologous recombination and non-homologous end joining, including RNF168, 53BP1, BRCA1 and RAD51. Mechanistically, WRAP53β accomplishes this by facilitating the necessary ubiquitinylation at DNA breaks. Finally, we demonstrate that loss of WRAP53β significantly impairs the repair of DNA double-strand breaks, resulting in their accumulation. Our findings establish WRAP53β as a regulator of homologous recombination and non-homologous end joining repair in ovarian cancer cells, suggesting that loss of this protein contributes to the development and/or progression of ovarian tumors. Moreover, our current observations identify the nuclear levels of WRAP53β as a promising biomarker for the survival of patients with ovarian cancer.

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  • Cancer and Oncology
Original languageEnglish
Article numbere1892
JournalCell Death & Disease
Volume6
Publication statusPublished - 2015
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Faculty of Medicine (000022000), Pathology, (Lund) (013030000)

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