The genomic landscape of cancer is one marred by instability, but the mechanisms that underlie these alterations are multifaceted and remain a topic of intense research. Cellular responses to DNA damage and/or replication stress can affect genome stability in tumors and influence the response of patients to therapy. In addition to direct repair, DNA damage tolerance (DDT) is an element of genomic maintenance programs that contributes to the etiology of several types of cancer. DDT mechanisms primarily act to resolve replication stress, and this can influence the effectiveness of genotoxic drugs. Translesion DNA synthesis (TLS) is an important component of DDT that facilitates direct bypass of DNA adducts and other barriers to replication. The central role of TLS in the bypass of drug-induced DNA lesions, the promotion of tumor heterogeneity, and the involvement of these enzymes in the maintenance of the cancer stem cell niche presents an opportunity to leverage inhibition of TLS as a way of improving existing therapies. In the review that follows, we summarize mechanisms of DDT, misregulation of TLS in cancer, and discuss the potential for targeting these pathways as a means of improving cancer therapies.

中文翻译：

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癌症中的跨病变DNA合成：分子机制和治疗机会。

癌症的基因组格局是不稳定造成的，但这些改变背后的机制却是多方面的，仍然是深入研究的主题。细胞对DNA损伤和/或复制压力的反应会影响肿瘤中的基因组稳定性，并影响患者对治疗的反应。除了直接修复外，DNA损伤耐受性（DDT）是基因组维护程序的一个要素，它有助于多种癌症的病因学。滴滴涕机制主要起解决复制压力的作用，这可能会影响遗传毒性药物的有效性。跨病害DNA合成（TLS）是DDT的重要组成部分，它有助于直接绕过DNA加合物和其他复制障碍。TLS在绕过药物诱导的DNA损伤，促进肿瘤异质性，这些酶参与癌症干细胞生态位的维持提供了利用TLS抑制作为改进现有疗法的机会。在随后的综述中，我们总结了滴滴涕的机制，癌症中TLS的失调，并讨论了靶向这些途径作为改善癌症治疗手段的潜力。