Downregulation of the cancer susceptibility protein WRAP53β in epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome.
Hedström, E ; Pederiva, C ; Farnebo, J ; Nodin, Björn LU ; Jirström, Karin LU
; Brennan, D J
and Farnebo, M
(2015)
In Cell Death & Disease
6.
- 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.... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8159774
- author
- Hedström, E
; Pederiva, C
; Farnebo, J
; Nodin, Björn
LU
; Jirström, Karin
LU
; Brennan, D J
and Farnebo, M
- organization
- publishing date
- 2015
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Death & Disease
- volume
- 6
- article number
- e1892
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:26426684
- wos:000367150100001
- scopus:84943189781
- pmid:26426684
- ISSN
- 2041-4889
- DOI
- 10.1038/cddis.2015.250
- language
- English
- LU publication?
- yes
- additional info
- 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)
- id
- 4ab09fbd-c515-4270-a2b6-ac1a055d8da1 (old id 8159774)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/26426684?dopt=Abstract
- date added to LUP
- 2016-04-01 14:39:43
- date last changed
- 2024-01-29 02:52:09
@article{4ab09fbd-c515-4270-a2b6-ac1a055d8da1,
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.}},
author = {{Hedström, E and Pederiva, C and Farnebo, J and Nodin, Björn and Jirström, Karin and Brennan, D J and Farnebo, M}},
issn = {{2041-4889}},
language = {{eng}},
publisher = {{Nature Publishing Group}},
series = {{Cell Death & Disease}},
title = {{Downregulation of the cancer susceptibility protein WRAP53β in epithelial ovarian cancer leads to defective DNA repair and poor clinical outcome.}},
url = {{https://lup.lub.lu.se/search/files/4093860/8840935}},
doi = {{10.1038/cddis.2015.250}},
volume = {{6}},
year = {{2015}},
}