Physiological role of protein-protein interaction among translesion DNA polymerases in cellular resistance to ultraviolet light

DNA聚合酶η (Polη)对环丁烷嘧啶二聚体（CPD）进行了准确、高效的TLS检测，其基因突变是遗传性色素干皮病变异（XP-V）的主要原因。由于Polη与Polι和REV1相互作用，我们认为Polη在这些TLS聚合酶在病变部位的募集中起作用。但目前尚不清楚XP-V患者的UV敏感性是否除了Polη活性缺陷外，还与Polη与其他TLS聚合酶之间的网络功能障碍有关。在这里，我们研究了通过Polη的TLS聚合酶网络是否对CPDs的复制绕过和紫外线诱导的DNA损伤耐受性有重要作用。我们观察到无活性Polη的表达适度地恢复了Polη缺失小鼠细胞的紫外线敏感性。此外，这种细胞紫外线敏感性的恢复是由Polη和REV1相互作用介导的。然而，失活突变体Polη的表达不能抑制在Polη缺乏细胞中观察到的紫外线诱导突变的惊人发生率。最后，我们证明了当Polη不能绕过其同源底物时，REV1和Polκ通过Polη-REV1相互作用参与诱变DNA损伤耐受。

DNA polymerase η (Polη), whose gene mutation is responsible for the inherited disorder xeroderma pigmentosum variant (XP-V), carries out accurate and efficient TLS against cyclobutane pyrimidine dimer (CPD). Since Polη interacts with Polι and REV1, it is suggested that Polη plays a role in recruitment of these TLS polymerases at lesion site. But it is unclear whether UV sensitivity of XP-V patients is caused not only by defect of Polη activity but also by dysfunction of network between Polη and other TLS polymerases. Here, we examined whether the TLS polymerase network via Polη is important for replicative bypass of CPDs and DNA damage tolerance induced by UV in mouse cells. We observed that UV sensitivity of Polη-deficient mouse cells was moderately rescued by the expression of inactive Polη. Moreover, this recovery of cellular UV sensitivity was mediated by the interaction between Polη and REV1. However, expression of inactive mutant Polη was not able to suppress the striking incidence of UV-induced mutation observed in Polη-deficient cells. Finally we demonstrated that REV1 and Polκ are involved in mutagenic DNA damage tolerance via Polη-REV1 interaction when Polη was failed to bypass its cognate substrates.