DNA Polymerase η, a Key Protein in Translesion Synthesis in Human Cells
DNA Polymerase η, a Key Protein in Translesion Synthesis in Human Cells
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DOI：
10.1007/978-90-481-3471-7_10
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发表时间：
2010-01-01
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影响因子：
--
通讯作者：
Carty, Michael P.
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文献类型：
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作者：
Cruet-Hennequart, Severine;Gallagher, Kathleen;Carty, Michael P.
基因组DNA由于暴露于外源性和内源性试剂而不断受到损伤。模板DNA中的大体积加合物如UV诱导的环丁烷嘧啶二聚体（CPD）对主要真核复制聚合酶（包括DNA聚合酶δ）的DNA合成呈现屏障。翻译合成（TLS）是一种进化上保守的DNA损伤耐受机制。DNA聚合酶的Y家族，包括DNA聚合酶eta（Pol eta），本章的主题，在TLS中发挥关键作用。编码Pol eta的人POLH基因突变是遗传性疾病着色性干皮病变体（XPV）的基础，其特征在于阳光敏感性、皮肤癌发病率升高，以及在细胞水平上，在UV照射后延迟复制和超突变性。当复制未受损的DNA时，Pol eta是一种低保真度酶，但可以在UV诱导的二胸腺嘧啶CPD位点进行无错误的TLS。Pol eta的活性位点具有开放构象，可以容纳CPD以及顺铂诱导的链内DNA交联。Pol eta通过与PCNA相互作用在严格调控的过程中被招募到复制停滞位点。Poleta缺陷细胞显示出下游DNA损伤应答（包括ATR信号传导）的强烈激活，并且由于复制叉崩溃而积累链断裂。因此，Pol eta在防止UV和顺铂诱导的DNA损伤后的基因组不稳定性中起重要作用。抑制肿瘤中的DNA损伤耐受途径也可能代表了一种增强DNA损伤剂如顺铂的作用的方法。
Genomic DNA is constantly damaged by exposure to exogenous and endogenous agents. Bulky adducts such as UV-induced cyclobutane pyrimidine dimers (CPDs) in the template DNA present a barrier to DNA synthesis by the major eukaryotic replicative polymerases including DNA polymerase delta. Translesion synthesis (TLS) carried out by specialized DNA polymerases is an evolutionarily conserved mechanism of DNA damage tolerance. The Y family of DNA polymerases, including DNA polymerase eta (Pol eta), the subject of this chapter, play a key role in TLS. Mutations in the human POLH gene encoding Pol eta underlie the genetic disease xeroderma pigmentosum variant (XPV), characterized by sun sensitivity, elevated incidence of skin cancer, and at the cellular level, by delayed replication and hypermutability after UV-irradiation. Pol eta is a low fidelity enzyme when copying undamaged DNA, but can carry out error-free TLS at sites of UV-induced dithymine CPDs. The active site of Pol eta has an open conformation that can accommodate CPDs, as well as cisplatin-induced intrastrand DNA crosslinks. Pol eta is recruited to sites of replication arrest in a tightly regulated process through interaction with PCNA. Pol eta-deficient cells show strong activation of downstream DNA damage responses including ATR signaling, and accumulate strand breaks as a result of replication fork collapse. Thus, Pol eta plays an important role in preventing genome instability after UV- and cisplatin-induced DNA damage. Inhibition of DNA damage tolerance pathways in tumors might also represent an approach to potentiate the effects of DNA damaging agents such as cisplatin.