Hedström E, Pederiva C, Farnebo J, Nodin B, Jirström K, Brennan D J, Farnebo M
Department of Oncology-Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden.
Department of Diagnostic Radiology, Karolinska University Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Cell Death Dis. 2015 Oct 1;6(10):e1892. doi: 10.1038/cddis.2015.250.
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.
支架蛋白WRAP53β的改变先前已与致癌作用相关联，尤其是与上皮性卵巢癌风险增加有关。在此，我们研究了WRAP53β在上皮性卵巢癌中的致病影响和预后意义，并探讨了其潜在机制。我们发现卵巢肿瘤中WRAP53β表达降低与DNA损伤反应减弱及患者预后不良相关。此外，在卵巢癌细胞系中，WRAP53β迅速被招募至DNA双链断裂处，在那里它协调参与同源重组和非同源末端连接的修复因子的招募，包括RNF168、53BP1、BRCA1和RAD51。从机制上讲，WRAP53β通过促进DNA断裂处必要的泛素化来实现这一点。最后，我们证明WRAP53β的缺失显著损害DNA双链断裂的修复，导致其积累。我们的研究结果确立了WRAP53β作为卵巢癌细胞中同源重组和非同源末端连接修复的调节因子，表明该蛋白的缺失有助于卵巢肿瘤的发生和/或进展。此外，我们目前的观察结果确定WRAP53β的核水平是卵巢癌患者生存的一个有前景的生物标志物。
