Stalled Pol? at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1
Stalled Pol? at its cognate substrate initiates an alternative translesion synthesis pathway via interaction with REV1
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DOI：
10.1111/j.1365-2443.2011.01576.x
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发表时间：
2012-02-01
期刊：
影响因子：
2.1
通讯作者：
Hanaoka, Fumio
中科院分区：
文献类型：
--
作者：
Ito, Wakana;Yokoi, Masayuki;Hanaoka, Fumio
DNA 聚合酶 ? (Pol?) 的基因突变导致遗传性疾病着色性干皮病变体 (XP-V)，它可以跨环丁烷嘧啶二聚体 (CPD) 进行准确有效的跨病灶合成 (TLS)。作为波尔?与 REV1 相互作用，REV1 与其他 TLS 聚合酶包括 Pol?、Pol? 相互作用。和波尔？，波尔？可能在损伤部位募集这些 TLS 聚合酶中发挥作用。但尚不清楚 XP-V 患者的紫外线敏感性是否不仅是由 Pol? 缺陷引起的？活动也受到 Pol 之间网络功能障碍的影响。和其他 TLS 聚合酶。在这里，我们检查了 TLS 聚合酶网络是否通过 Pol？对于小鼠细胞中 CPD 的复制旁路和 UV 诱导的 DNA 损伤耐受性很重要。我们观察到，表达无催化活性的 Pol? 可以适度恢复 Pol? 缺陷小鼠细胞的紫外线敏感性。此外，细胞紫外线敏感性的恢复是由 Pol? 之间的相互作用介导的。和 REV1。然而，失活突变体 Pol? 的表达？无法抑制在 Pol? 缺陷细胞中观察到的紫外线诱导突变的发生率。我们提出了 REV1 和 Pol？当 Pol?REV1 相互作用时，参与 DNA 损伤耐受。无法绕过其同源底物。
DNA polymerase ? (Pol?), whose gene mutation is responsible for the inherited disorder xeroderma pigmentosum variant (XP-V), carries out accurate and efficient translesion synthesis (TLS) across cyclobutane pyrimidine dimer (CPD). As Pol? interacts with REV1, and REV1 interacts with other TLS polymerases including Pol?, Pol? and Pol?, Pol? may play 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 Pol? activity but also by dysfunction of network between Pol? and other TLS polymerases. Here, we examined whether the TLS polymerase network via Pol? is important for replicative bypass of CPDs and DNA damage tolerance induced by UV in mouse cells. We observed that UV sensitivity of Pol?-deficient mouse cells was moderately rescued by the expression of a catalytically inactive Pol?. Moreover, this recovery of cellular UV sensitivity was mediated by the interaction between Pol? and REV1. However, expression of the inactive mutant Pol? was not able to suppress the incidence of UV-induced mutation observed in Pol?-deficient cells. We propose the model that REV1 and Pol? are involved in DNA damage tolerance via Pol?REV1 interaction when Pol? fails to bypass its cognate substrates.