Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Mol Pharmacol. 2012 Jun;81(6):778-87. doi: 10.1124/mol.111.076828. Epub 2012 Mar 2.
Oxaliplatin, satraplatin, and picoplatin are cisplatin analogs that interact with DNA forming intrastrand and interstrand DNA cross-links (ICLs). Replicative bypass of cisplatin DNA adducts requires the cooperative actions of at least three translesion DNA synthesis (TLS) polymerases: Polη, REV1, and Polζ. Because oxaliplatin, satraplatin, and picoplatin contain bulkier chemical groups attached to the platinum core compared with cisplatin, we hypothesized that these chemical additions may impede replicative bypass by TLS polymerases and reduce tolerance to platinum-containing adducts. We examined multiple responses of cancer cells to oxaliplatin, satraplatin, or picoplatin treatment under conditions where expression of a TLS polymerase was limited. Our studies revealed that, although Polη contributes to the tolerance of cisplatin adducts, it plays a lesser role in promoting replication through oxaliplatin, satraplatin, and picoplatin adducts. REV1 and Polζ were necessary for tolerance to all four platinum analogs and prevention of hyperactivation of the DNA damage response after treatment. In addition, REV1 and Polζ were important for the resolution of DNA double-stranded breaks created during replication-associated repair of platinum-containing ICLs. Consistent with ICLs being the predominant cytotoxic lesion, depletion of REV1 or Polζ rendered two different model cell systems extremely sensitive to all four drugs, whereas Polη depletion had little effect. Together, our data suggest that REV1 and Polζ are critical for promoting resistance to all four clinically relevant platinum-based drugs by promoting both translesion DNA synthesis and DNA repair.
奥沙利铂、沙铂和比铂是顺铂类似物，它们与 DNA 相互作用形成链内和链间 DNA 交联（ICLs）。复制旁路顺铂 DNA 加合物需要至少三种跨损伤 DNA 合成（TLS）聚合酶的协同作用：Polη、REV1 和 Polζ。由于奥沙利铂、沙铂和比铂与顺铂相比，在铂核上附着了更大的化学基团，我们假设这些化学添加物可能会阻碍 TLS 聚合酶的复制旁路，并降低对含铂加合物的耐受性。我们在限制 TLS 聚合酶表达的条件下，研究了癌细胞对奥沙利铂、沙铂或比铂处理的多种反应。我们的研究表明，虽然 Polη 有助于顺铂加合物的耐受，但它在促进通过奥沙利铂、沙铂和比铂加合物的复制方面作用较小。REV1 和 Polζ 对于耐受所有四种铂类似物和防止治疗后 DNA 损伤反应的过度激活都是必需的。此外，REV1 和 Polζ 对于复制相关修复含铂 ICLs 期间形成的 DNA 双链断裂的解决也很重要。与 ICLs 是主要的细胞毒性损伤一致，REV1 或 Polζ 的耗竭使两个不同的模型细胞系统对所有四种药物极其敏感，而 Polη 的耗竭几乎没有影响。总之，我们的数据表明，REV1 和 Polζ 通过促进跨损伤 DNA 合成和 DNA 修复，对于促进对所有四种临床相关铂类药物的耐药性至关重要。
