Bifunctional alkylating and platinum based drugs are chemotherapeutic agents used to treat cancer. These agents induce DNA adducts via formation of intrastrand or interstrand (ICL) DNA crosslinks, and DNA lesions of the ICL type are particularly toxic as they block DNA replication and/or DNA transcription. However, the therapeutic efficacies of these drugs are frequently limited due to the cancer cell's enhanced ability to repair and tolerate these toxic DNA lesions. This ability to tolerate and survive the DNA damage is accomplished by a set of specialized low fidelity DNA polymerases called translesion synthesis (TLS) polymerases since high fidelity DNA polymerases are unable to replicate the damaged DNA template. TLS is a crucial initial step in ICL repair as it synthesizes DNA across the lesion thus preparing the damaged DNA template for repair by the homologous recombination (HR) pathway and Fanconi anemia (FA) network, processes critical for ICL repair. Here we review the molecular features and functional roles of TLS polymerases, discuss the collaborative interactions and cross-regulation of the TLS DNA damage tolerance pathway, the FA network and the BRCA-dependent HRR pathway, and the impact of TLS hyperactivation on development of chemoresistance. Finally, since TLS hyperactivation results from overexpression of Rad6/Rad18 ubiquitinating enzymes (fundamental components of the TLS pathway), increased PCNA ubiquitination, and/or increased recruitment of TLS polymerases, the potential benefits of selectively targeting critical components of the TLS pathway for enhancing anti-cancer therapeutic efficacy and curtailing chemotherapy-induced mutagenesis are also discussed.

中文翻译：

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跨损伤合成、范可尼贫血网络和链间 DNA 交联修复和化学抗性发展中的同源重组修复途径之间的串扰。

双功能烷基化和铂类药物是用于治疗癌症的化学治疗剂。这些试剂通过链内或链间 (ICL) DNA 交联的形成诱导 DNA 加合物，ICL 类型的 DNA 损伤特别有毒，因为它们会阻止 DNA 复制和/或 DNA 转录。然而，由于癌细胞修复和耐受这些有毒 DNA 损伤的能力增强，这些药物的治疗效果经常受到限制。这种耐受 DNA 损伤并使其存活的能力是由一组称为转移损伤合成 (TLS) 聚合酶的专门低保真 DNA 聚合酶实现的，因为高保真 DNA 聚合酶无法复制受损的 DNA 模板。TLS 是 ICL 修复的关键初始步骤，因为它跨病变合成 DNA，从而准备受损的 DNA 模板以通过同源重组 (HR) 途径和范可尼贫血 (FA) 网络进行修复，这对 ICL 修复至关重要。在这里，我们回顾了 TLS 聚合酶的分子特征和功能作用，讨论了 TLS DNA 损伤耐受途径、FA 网络和 BRCA 依赖性 HRR 途径的协同相互作用和交叉调节，以及 TLS 过度激活对化学抗性发展的影响. 最后，由于 TLS 过度激活是由 Rad6/Rad18 泛素化酶（TLS 途径的基本组成部分）的过度表达、PCNA 泛素化增加和/或 TLS 聚合酶募集增加引起的，