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

DNA聚合酶η(PolDNA聚合酶η)是导致遗传性色素性干皮病(XP-V)的基因突变，它对环丁烷嘧啶二聚体(CPD)进行准确而有效的热释光。由于POLη与POLι和REV1相互作用，推测POLη在病变部位对这些TLS聚合酶的募集起作用。但目前尚不清楚XP-V患者对紫外线的敏感性是否不仅是由于POLη活性缺陷引起的，还是由于POLη与其他TLS聚合酶之间的网络功能障碍所致。在这里，我们研究了通过POLη的TLS聚合酶网络对于CPD的复制旁路和紫外线诱导的小鼠细胞DNA损伤耐受性是否重要。我们观察到POLη缺陷小鼠细胞对紫外线的敏感性可通过表达失活的POLη适度恢复。此外，这种细胞紫外线敏感性的恢复是由POLη和Rev1之间的相互作用所介导的。然而，表达失活突变体Polη不能抑制在Polη缺陷细胞中观察到的紫外线诱导突变的显著发生率。最后，我们证明了当POLκ不能绕过其同源底物时，通过POLη与REV1的相互作用，POLη参与了突变耐受。

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.