PCNA trimer instability inhibits translesion synthesis by DNA polymerase η and by DNA polymerase δ.
PCNA trimer instability inhibits translesion synthesis by DNA polymerase η and by DNA polymerase δ.
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DOI：
10.1016/j.dnarep.2013.02.007
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发表时间：
2013-05-01
期刊：
影响因子：
3.8
通讯作者：
Washington, M. Todd
中科院分区：
文献类型：
--
作者：
Dieckman, Lynne M.;Washington, M. Todd
转录合成（TLS），DNA聚合酶通过DNA损伤复制的过程，是大多数DNA损伤诱导突变的来源。有时TLS是由复制聚合酶进行的，这些聚合酶已经进化到在未受损的模板上合成DNA。然而，大多数情况下，TLS是由专门的translesion聚合酶进行的，这些聚合酶已经进化到在受损的模板上合成DNA。TLS需要复制辅助因子增殖细胞核抗原（PCNA）的单泛素化。PCNA和泛素修饰的PCNA（UbPCNA）通过复制和跨损伤聚合酶刺激TLS。PCNA的两种突变形式，一种具有E113G取代，一种具有G178S取代，支持正常细胞生长，但抑制TLS，从而减少酵母中的诱变。两种突变型PCNA蛋白的结构的重新检查揭示了形成PCNA三聚体的亚基界面的实质性破坏。这两种突变蛋白具有降低的三聚体稳定性，其中G178S取代导致更严重的缺陷。PCNA和UbPCNA的突变形式不通过复制Pol δ或跨损伤Pol η刺激脱碱基位点的TLS。Pol η的正常复制也受到影响，但Pol δ的正常复制受到的影响要小得多。这些研究结果支持一个模型，其中减少三聚体稳定性导致这些突变的PCNA蛋白偶尔发生构象变化，损害他们的能力，刺激TLS的复制和translesion聚合酶。
Translesion synthesis (TLS), the process by which DNA polymerases replicate through DNA lesions, is the source of most DNA damage-induced mutations. Sometimes TLS is carried out by replicative polymerases that have evolved to synthesize DNA on non-damaged templates. Most of the time, however, TLS is carried out by specialized translesion polymerases that have evolved to synthesize DNA on damaged templates. TLS requires the mono-ubiquitylation of the replication accessory factor proliferating cell nuclear antigen (PCNA). PCNA and ubiquitin-modified PCNA (UbPCNA) stimulate TLS by replicative and translesion polymerases. Two mutant forms of PCNA, one with an E113G substitution and one with a G178S substitution, support normal cell growth but inhibit TLS thereby reducing mutagenesis in yeast. A re-examination of the structures of both mutant PCNA proteins revealed substantial disruptions of the subunit interface that forms the PCNA trimer. Both mutant proteins have reduced trimer stability with the G178S substitution causing a more severe defect. The mutant forms of PCNA and UbPCNA do not stimulate TLS of an abasic site by either replicative Pol δ or translesion Pol η. Normal replication by Pol η was also impacted, but normal replication by Pol δ was much less affected. These findings support a model in which reduced trimer stability causes these mutant PCNA proteins to occasionally undergo conformational changes that compromise their ability to stimulate TLS by both replicative and translesion polymerases.
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影响因子：
19
作者：
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通讯作者：
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影响因子：
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DOI：
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通讯作者：
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作者：
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