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.
Highlights
Alteration of the DNA damage response is one major factor in the onset and/or progression of ovarian cancer
Repair by homologous recombination (HR) is defective in approximately half of all ovarian tumors due to inactivation of genes encoding proteins involved in this pathway, such as breast cancer 1 (BRCA1) and BRCA2.2 Since HR is involved in repairing DNA lesions caused by platinum-based chemotherapeutics and poly ADP-ribose polymerase (PARP) inhibitors, HR-deficient tumors are hypersensitive to these drugs, which help prolong patient survival,[3,4] perhaps for not more than 5 years.[5,6,7]
We demonstrate that WRAP53β participates in DNA repair in epithelial ovarian cancer cell lines by targeting factors involved in the HR and non-homologous end joining (NHEJ) pathways to such DNA lesions and that loss of this protein eliminates repair of DNA double-strand breaks
Summary
Alteration of the DNA damage response is one major factor in the onset and/or progression of ovarian cancer. Repair by homologous recombination (HR) is defective in approximately half of all ovarian tumors due to inactivation of genes encoding proteins involved in this pathway, such as BRCA1 and BRCA2.2 Since HR is involved in repairing DNA lesions caused by platinum-based chemotherapeutics and poly ADP-ribose polymerase (PARP) inhibitors, HR-deficient tumors are hypersensitive to these drugs, which help prolong patient survival,[3,4] perhaps for not more than 5 years.[5,6,7]. Inactivation of HR enhances NHEJ repair and overstimulation of this error-prone pathway was recently shown to contribute to the hypersensitivity of HRdeficient ovarian tumors to PARP inhibitors.[8,9] Consistent with this observation, inactivation of NHEJ through inhibition of DNA-PK/Ku80 or deletion of 53BP1 abrogates the cytotoxicity and genomic instability induced by PARP inhibitors leading to drug resistance.[8,9] impairment of NHEJ in HR-deficient tumors could result in resistance to treatment and reduce patient survival. Received 25.5.2015; revised 27.7.2015; accepted 31.7.2015; Edited by A Oberst was recently shown to control the repair of DNA doublestrand breaks by both the HR and NHEJ pathways through targeting the critical ubiquitin ligase RNF8 to these lesions.[14]
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