Replication Protein A Availability during DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells
Replication Protein A Availability during DNA Replication Stress Is a Major Determinant of Cisplatin Resistance in Ovarian Cancer Cells
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DOI：
10.1158/0008-5472.can-18-0618
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发表时间：
2018-10-01
期刊：
影响因子：
11.2
通讯作者：
Drobetsky, Elliot
中科院分区：
文献类型：
--
作者：
Belanger, Francois;Fortier, Emile;Drobetsky, Elliot
对顺铂的内在和获得性耐药仍然是治疗高级别浆液性卵巢癌（HGSOC）的主要障碍。顺铂通过诱导阻断DNA聚合酶复制的DNA交联选择性地杀死肿瘤细胞。在所产生的停滞复制叉（RF）处产生的单链DNA（ssDNA）被异源三聚体复制蛋白A（RPA）结合并保护，其然后用作复制应激反应因子的募集和激活的平台。缺乏这种反应的细胞的特征在于大量ssDNA形成和过量RPA募集，其耗尽了RPA的可用池，这（i）抑制RPA依赖性过程，如核苷酸切除修复（NER）和（ii）导致阻断的RF的灾难性失败。在这里，我们使用一组人类HGSOC细胞系研究了RPA的可用性对化学敏感性的影响。我们的数据揭示了这些细胞系之间的顺铂敏感性和无法有效地修复DNA通过NER，特别是在S期之间的显着相关性。NER中的这种缺陷可归因于在复制应激期间DNA复制起点的异常激活所产生的RPA耗尽。在对顺铂敏感性升高的细胞系中，RPA可用性降低促进了Mre11依赖性的新生DNA在停滞RF下的降解。引人注目的是，有缺陷的S期NER，RF不稳定性，顺铂敏感性都可以通过RPA的异位过表达来挽救。两者合计，我们的研究结果表明，RPA耗尽代表了一个主要的决定因素，顺铂敏感性在HGSOC细胞line.Significance：复制蛋白A耗尽对顺铂敏感性的影响，对改善治疗的各种癌症，最初响应铂类药物，但后来复发，由于内在或获得性耐药的重要意义。(C)2018年AACR。
Intrinsic and acquired resistance to cisplatin remains a primary hurdle to treatment of high-grade serous ovarian cancer (HGSOC). Cisplatin selectively kills tumor cells by inducing DNAcrosslinks that block replicativeDNApolymerases. Single-stranded DNA (ssDNA) generated at resulting stalled replication forks (RF) is bound and protected by heterotrimeric replication protein A (RPA), which then serves as a platform for recruitment and activation of replication stress response factors. Cells deficient in this response are characterized by extensive ssDNA formation and excessive RPA recruitment that exhausts the available pool of RPA, which (i) inhibits RPAdependent processes such as nucleotide excision repair (NER) and (ii) causes catastrophic failure of blocked RF. Here, we investigated the influence of RPA availability on chemosensitivity using a panel of human HGSOC cell lines. Our data revealed a striking correlation among these cell lines between cisplatin sensitivity and the inability to efficiently repair DNA via NER, specifically during S phase. Such defects in NER were attributable to RPA exhaustion arising from aberrant activation of DNA replication origins during replication stress. Reduced RPA availability promoted Mre11-dependent degradation of nascent DNA at stalled RF in cell lines exhibiting elevated sensitivity to cisplatin. Strikingly, defective S-phase NER, RF instability, and cisplatin sensitivity could all be rescued by ectopic overexpression of RPA. Taken together, our findings indicate that RPA exhaustion represents a major determinant of cisplatin sensitivity in HGSOC cell lines.Significance: The influence of replication protein A exhaustion on cisplatin sensitivity harbors important implications toward improving therapy of various cancers that initially respond to platinum-based agents but later relapse due to intrinsic or acquired drug resistance. (C) 2018 AACR.