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Platinum-Induced Ubiquitination of Phosphorylated H2AX by RING1A is Mediated by Replication Protein A in Ovarian Cancer
Molecular Cancer Research ( IF 5.2 ) Pub Date : 2020-08-14 , DOI: 10.1158/1541-7786.mcr-20-0396
Shruthi Sriramkumar 1 , Timothy D Matthews 1 , Ahmed H Ghobashi 2 , Samuel A Miller 2 , Pamela S VanderVere-Carozza 3 , Katherine S Pawelczak 4 , Kenneth P Nephew 1, 5, 6 , John J Turchi 3, 5 , Heather M O'Hagan 1, 5, 7
Affiliation  

Platinum resistance is a common occurrence in high-grade serous ovarian cancer and a major cause of ovarian cancer deaths. Platinum agents form DNA cross-links, which activate nucleotide excision repair (NER), Fanconi anemia, and homologous recombination repair (HRR) pathways. Chromatin modifications occur in the vicinity of DNA damage and play an integral role in the DNA damage response (DDR). Chromatin modifiers, including polycomb repressive complex 1 (PRC1) members, and chromatin structure are frequently dysregulated in ovarian cancer and can potentially contribute to platinum resistance. However, the role of chromatin modifiers in the repair of platinum DNA damage in ovarian cancer is not well understood. We demonstrate that the PRC1 complex member RING1A mediates monoubiquitination of lysine 119 of phosphorylated H2AX (γH2AXub1) at sites of platinum DNA damage in ovarian cancer cells. After platinum treatment, our results reveal that NER and HRR both contribute to RING1A localization and γH2AX monoubiquitination. Importantly, replication protein A, involved in both NER and HRR, mediates RING1A localization to sites of damage. Furthermore, RING1A deficiency impairs the activation of the G2–M DNA damage checkpoint, reduces the ability of ovarian cancer cells to repair platinum DNA damage, and increases sensitivity to platinum. Implications: Elucidating the role of RING1A in the DDR to platinum agents will allow for the identification of therapeutic targets to improve the response of ovarian cancer to standard chemotherapy regimens.

中文翻译:

RING1A 对磷酸化 H2AX 的铂诱导泛素化是由卵巢癌中的复制蛋白 A 介导的

铂耐药是高级别浆液性卵巢癌的常见现象,也是卵巢癌死亡的主要原因。铂剂形成 DNA 交联,激活核苷酸切除修复 (NER)、范可尼贫血和同源重组修复 (HRR) 途径。染色质修饰发生在 DNA 损伤附近,并在 DNA 损伤反应 (DDR) 中发挥不可或缺的作用。染色质修饰剂,包括多梳抑制复合物 1 (PRC1) 成员和染色质结构在卵巢癌中经常失调,并可能导致铂耐药。然而,染色质修饰剂在修复卵巢癌铂 DNA 损伤中的作用尚不清楚。我们证明,PRC1 复合物成员 RING1A 在卵巢癌细胞中铂 DNA 损伤位点介导磷酸化 H2AX (γH2AXub1) 赖氨酸 119 的单泛素化。铂处理后,我们的结果表明 NER 和 HRR 都有助于 RING1A 定位和 γH2AX 单泛素化。重要的是,参与 NER 和 HRR 的复制蛋白 A 介导 RING1A 定位到损伤部位。此外,RING1A 缺陷会损害 G2-M DNA 损伤检查点的激活,降低卵巢癌细胞修复铂 DNA 损伤的能力,并增加对铂的敏感性。意义:阐明 RING1A 在 DDR 到铂类药物中的作用将有助于确定治疗靶点,以改善卵巢癌对标准化疗方案的反应。
更新日期:2020-08-14
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