The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight.
The identification of translesion DNA synthesis regulators: Inhibitors in the spotlight.
复制标题
DOI：
10.1016/j.dnarep.2015.04.027
复制
发表时间：
2015-08
期刊：
影响因子：
3.8
通讯作者：
Gottifredi V
中科院分区：
文献类型：
--
作者：
Bertolin AP;Mansilla SF;Gottifredi V
在过去的半个世纪里，我们越来越意识到DNA损伤的普遍性。在持续暴露于外源性和内源性基因组应激下，细胞必须尝试复制受损的DNA。复制叉与DNA损伤的相遇触发了几种细胞反应，包括跨损伤DNA合成（TLS）的激活，这在很大程度上取决于具有能够容纳大体积DNA损伤的灵活活性位点的专门DNA聚合酶。TLS的一个不利方面是其固有的致突变性质，因此TLS聚合酶的活性必须理想地限于在受损DNA模板上的合成。尽管TLS抑制剂在化疗中具有潜在的临床重要性，但由于仍无法获得旨在量化基因组TLS事件的直接测定，因此难以鉴定TLS抑制剂。在本文中，我们讨论了已用于验证TLS抑制剂（如USP 1，p21和Spartan）的方法，重点介绍了它们对控制受损和未受损模板上DNA合成的贡献。
Over the past half-century, we have become increasingly aware of the ubiquity of DNA damage. Under the constant exposure to exogenous and endogenous genomic stress, cells must attempt to replicate damaged DNA. The encounter of replication forks with DNA lesions triggers several cellular responses, including the activation of translesion DNA synthesis (TLS), which largely depends upon specialized DNA polymerases with flexible active sites capable of accommodating bulky DNA lesions. A detrimental aspect of TLS is its intrinsic mutagenic nature, and thus the activity of the TLS polymerases must ideally be restricted to synthesis on damaged DNA templates. Despite their potential clinical importance in chemotherapy, TLS inhibitors have been difficult to identify since a direct assay designed to quantify genomic TLS events is still unavailable. Herein we discuss the methods that have been used to validate TLS inhibitors such as USP1, p21 and Spartan, highlighting research that has revealed their contribution to the control of DNA synthesis on damaged and undamaged templates.