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

Hedstrom, E., Pederiva, C., Farnebo, J., Nodin, B., Jirstrom, K., Brennan, D. J. and Farnebo, M. (2015) Downregulation of the cancer susceptibility protein WRAP53β in epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome. Cell Death and Disease, 6 1892.1-1892.9. doi:10.1038/cddis.2015.250


Author Hedstrom, E.
Pederiva, C.
Farnebo, J.
Nodin, B.
Jirstrom, K.
Brennan, D. J.
Farnebo, M.
Title Downregulation of the cancer susceptibility protein WRAP53β in epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome
Journal name Cell Death and Disease   Check publisher's open access policy
ISSN 2041-4889
Publication date 2015-10-01
Sub-type Article (original research)
DOI 10.1038/cddis.2015.250
Open Access Status DOI
Volume 6
Start page 1892.1
End page 1892.9
Total pages 9
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2016
Language eng
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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
 
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