A novel function of DNA polymerase ζ regulated by PCNA
A novel function of DNA polymerase ζ regulated by PCNA
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DOI：
10.1038/sj.emboj.7601320
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发表时间：
2006-09-20
期刊：
影响因子：
11.4
通讯作者：
Shcherbakova, Polina V.
中科院分区：
文献类型：
--
作者：
Northam, Matthew R.;Garg, Parie;Shcherbakova, Polina V.
DNA聚合酶zeta （Pol zeta）参与翻译DNA合成，并参与大多数DNA损伤引起的突变的产生。允许Pol zeta进入引物末端并调节其参与基因组复制的程度的机制尚不清楚。Pol - zeta依赖性损伤诱导诱变需要暴露于诱变剂引发的增殖细胞核抗原（PCNA）的单泛素化。我们发现，Pol zeta不仅对DNA损伤有贡献，而且在复制基因突变导致正常复制机制故障时也会引起突变。这些复制缺陷导致PCNA泛素化，即使在没有DNA损伤的情况下。与损伤诱导的诱变不同，复制突变体中Pol zeta依赖的自发诱变在PCNA泛素化和Lys164 sumo化缺陷的菌株中减少。此外，对与Pol zeta的功能相互作用有缺陷的PCNA突变体的研究表明，与Rad6/ Rad18复合物的单泛素化没有缺陷，PCNA在调节Pol zeta的致突变活性中发挥了作用，而Pol zeta在Lys164处被修饰。
DNA polymerase zeta (Pol zeta) participates in translesion DNA synthesis and is involved in the generation of the majority of mutations induced by DNA damage. The mechanisms that license access of Pol zeta to the primer terminus and regulate the extent of its participation in genome replication are poorly understood. The Pol zeta-dependent damage-induced mutagenesis requires monoubiquitination of proliferating cell nuclear antigen (PCNA) that is triggered by exposure to mutagens. We show that Pol zeta contributes to DNA replication and causes mutagenesis not only in response to DNA damage but also in response to malfunction of normal replicative machinery due to mutations in replication genes. These replication defects lead to ubiquitination of PCNA even in the absence of DNA damage. Unlike damage-induced mutagenesis, the Pol zeta-dependent spontaneous mutagenesis in replication mutants is reduced in strains defective in both ubiquitination and sumoylation of Lys164 of PCNA. Additionally, studies of a PCNA mutant defective for functional interactions with Pol zeta, but not for monoubiquitination by the Rad6/ Rad18 complex demonstrate a role for PCNA in regulating the mutagenic activity of Pol zeta separate from its modification at Lys164.