Chemotherapy with cisplatin becomes limiting due to toxicity and secondary malignancies. In principle, therapeutics could be improved by targeting translesion synthesis (TLS) polymerases (Pols) that promote replication through intrastrand cross-links, the major cisplatin-induced DNA adduct. However, to specifically target malignancies with minimal adverse effects on normal cells, a good understanding of TLS mechanisms in normal versus cancer cells is paramount. We show that in normal cells, TLS through cisplatin intrastrand cross-links is promoted by Polη- or Polι-dependent pathways, both of which require Rev1 as a scaffolding component. In contrast, cancer cells require Rev1-Polζ. Our findings that a recently identified Rev1 inhibitor, JH-RE-06, purported to specifically disrupt Rev1 interaction with Polζ to block TLS through cisplatin adducts in cancer cells, abrogates Rev1's ability to function with Y family Pols as well, implying that by inactivating Rev1-dependent TLS in normal cells, this inhibitor will exacerbate the toxicity and tumorigenicity of chemotherapeutics with cisplatin.

中文翻译：

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抑制 Rev1 与 Y 家族 DNA 聚合酶相互作用对顺铂化疗的影响

由于毒性和继发性恶性肿瘤，顺铂化疗变得有限。原则上，可以通过靶向跨损伤合成 (TLS) 聚合酶 (Pols) 来改进治疗方法，该聚合酶 (Pols) 通过链内交联（主要的顺铂诱导的 DNA 加合物）促进复制。然而，为了专门针对对正常细胞的不良影响最小的恶性肿瘤，对正常细胞与癌细胞中 TLS 机制的良好理解至关重要。我们表明，在正常细胞中，通过顺铂链内交联的 TLS 由 Polη 或 Polι 依赖性途径促进，这两种途径都需要 Rev1 作为支架成分。相反，癌细胞需要 Rev1-Polζ。我们的研究结果表明，最近发现的 Rev1 抑制剂 JH-RE-06，