DNA is constantly exposed to a wide variety of exogenous and endogenous agents, and most DNA lesions inhibit DNA synthesis. To cope with such problems during replication, cells have molecular mechanisms to resume DNA synthesis in the presence of DNA lesions, which are known as DNA damage tolerance (DDT) pathways. The concept of ubiquitination-mediated regulation of DDT pathways in eukaryotes was established via genetic studies in the yeast Saccharomyces cerevisiae, in which two branches of the DDT pathway are regulated via ubiquitination of proliferating cell nuclear antigen (PCNA): translesion DNA synthesis (TLS) and homology-dependent repair (HDR), which are stimulated by mono- and polyubiquitination of PCNA, respectively. Over the subsequent nearly two decades, significant progress has been made in understanding the mechanisms that regulate DDT pathways in other eukaryotes. Importantly, TLS is intrinsically error-prone because of the miscoding nature of most damaged nucleotides and inaccurate replication of undamaged templates by TLS polymerases (pols), whereas HDR is theoretically error-free because the DNA synthesis is thought to be predominantly performed by pol δ, an accurate replicative DNA pol, using the undamaged sister chromatid as its template. Thus, the regulation of the choice between the TLS and HDR pathways is critical to determine the appropriate biological outcomes caused by DNA damage. In this review, we summarize our current understanding of the species-specific regulatory mechanisms of PCNA ubiquitination and how cells choose between TLS and HDR. We then provide a hypothetical model for the spatiotemporal regulation of DDT pathways in human cells.

DNA不断暴露于各种各样的外源性和内源性物质，大多数DNA损伤会抑制DNA的合成。为了应对复制过程中的此类问题，细胞具有在存在DNA损伤的情况下恢复DNA合成的分子机制，这被称为DNA损伤耐受（DDT）途径。通过酿酒酵母中的遗传研究，建立了泛素介导的真核生物中DDT途径调控的概念。，其中DDT途径的两个分支是通过增殖细胞核抗原（PCNA）的泛素化来调节的：转移性DNA合成（TLS）和同源性依赖性修复（HDR），它们分别受PCNA的单泛素化和多泛素化作用刺激。在随后的近二十年中，在了解调节其他真核生物中滴滴涕途径的机制方面已取得重大进展。重要的是，由于大多数受损核苷酸的错误编码性质以及TLS聚合酶（pols）对未损坏模板的复制不准确，因此TLS本质上很容易出错，而HDR在理论上是无错误的，因为人们认为DNA合成主要由polδ进行。 ，一种精确的复制性DNA pol，使用未受损的姐妹染色单体作为模板。因此，TLS和HDR途径之间选择的调节对于确定由DNA损伤引起的适当生物学结果至关重要。在这篇综述中，我们总结了当前对PCNA泛素化的物种特异性调控机制以及细胞如何在TLS和HDR之间进行选择的理解。然后，我们为人类细胞中DDT途径的时空调节提供了一个假设模型。