Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
Department of Biochemistry & Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
DNA Repair (Amst). 2019 Jun;78:20-26. doi: 10.1016/j.dnarep.2019.03.016. Epub 2019 Mar 29.
DNA replication stress, defined as the slowing or stalling of replication forks, is considered an emerging hallmark of cancer and a major contributor to genomic instability associated with tumorigenesis (Macheret and Halazonetis, 2015). Recent advances have been made in attempting to target DNA repair factors involved in alleviating replication stress to potentiate genotoxic treatments. Various inhibitors of ATR and Chk1, the two major kinases involved in the intra-S-phase checkpoint, are currently in Phase I and II clinical trials [2]. In addition, currently approved inhibitors of Poly-ADP Ribose Polymerase (PARP) show synthetic lethality in cells that lack double-strand break repair such as in BRCA1/2 deficient tumors [3]. These drugs have also been shown to exacerbate replication stress by creating a DNA-protein crosslink, termed PARP 'trapping', and this is now thought to contribute to the therapeutic efficacy. Translesion synthesis (TLS) is a mechanism whereby special repair DNA polymerases accommodate and tolerate various DNA lesions to allow for damage bypass and continuation of DNA replication (Yang and Gao, 2018). This class of proteins is best characterized by the Y-family, encompassing DNA polymerases (Pols) Kappa, Eta, Iota, and Rev1. While best studied for their ability to bypass physical lesions on the DNA, there is accumulating evidence for these proteins in coping with various natural replication fork barriers and alleviating replication stress. In this mini-review, we will highlight some of these recent advances, and discuss why targeting the TLS pathway may be a mechanism of enhancing cancer-associated replication stress. Exacerbation of replication stress can lead to increased genome instability, which can be toxic to cancer cells and represent a therapeutic vulnerability.
DNA 复制压力，定义为复制叉的减速或停滞，被认为是癌症的一个新兴标志，也是与肿瘤发生相关的基因组不稳定性的主要原因（Macheret 和 Halazonetis，2015）。最近在试图靶向缓解复制压力的 DNA 修复因子方面取得了进展，以增强遗传毒性治疗。目前正在进行 I 期和 II 期临床试验，以评估涉及缓解复制压力的 ATR 和 Chk1 这两种主要的丝氨酸/苏氨酸激酶的各种抑制剂[2]。此外，目前批准的聚 ADP 核糖聚合酶（PARP）抑制剂在缺乏双链断裂修复的细胞中表现出合成致死性，例如在 BRCA1/2 缺陷肿瘤中[3]。这些药物还通过创建 DNA-蛋白质交联（称为 PARP“陷阱”）来加剧复制压力，这被认为有助于治疗效果。跨损伤合成（TLS）是一种特殊的修复 DNA 聚合酶能够适应和容忍各种 DNA 损伤的机制，从而允许绕过损伤并继续 DNA 复制（Yang 和 Gao，2018）。该蛋白家族的特征是 Y 家族，包括 DNA 聚合酶（Pols）Kappa、Eta、Iota 和 Rev1。虽然它们最常因能够绕过 DNA 上的物理损伤而被研究，但越来越多的证据表明这些蛋白在应对各种天然复制叉障碍和缓解复制压力方面具有作用。在这篇小型综述中，我们将重点介绍其中的一些最新进展，并讨论靶向 TLS 途径为何可能是增强与癌症相关的复制压力的一种机制。复制压力的加剧会导致基因组不稳定性增加，这对癌细胞有毒性，代表了一种治疗上的脆弱性。
