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The human papillomavirus DNA helicase E1 binds, stimulates, and confers processivity to cellular DNA polymerase epsilon
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2017-11-16 , DOI: 10.1093/nar/gkx1103
Michaelle Chojnacki , Thomas Melendy

The papillomavirus (PV) helicase protein E1 recruits components of the cellular DNA replication machinery to the PV replication fork, such as Replication Protein A (RPA), DNA polymerase α-primase (pol α) and topoisomerase I (topo I). Here we show that E1 binds to DNA polymerase ϵ (pol ϵ) and dramatically stimulates the DNA synthesis activity of pol ϵ. This stimulation of pol ϵ by E1 is highly specific and occurs even in the absence of the known pol ϵ cofactors Replication Factor C (RFC), Proliferating Cell Nuclear Antigen (PCNA) and RPA. This stimulation is due to an increase in the processivity of pol ϵ and occurs independently of pol ϵ’s replication cofactors. This increase in processivity is dependent on the ability of the E1 helicase to hydrolyze ATP, suggesting it is dependent on E1’s helicase action. In addition, RPA, thought to be vital for processive DNA synthesis by both pol ϵ and pol δ, was found to be dispensable for processive synthesis by pol ϵ in the presence of E1. Overall, E1 appears to be conferring processivity to pol ϵ by directly tethering pol ϵ to the DNA parental strand and towing ϵ behind the E1 helicase as the replication fork progresses; and thereby apparently obviating the need for RPA for leading strand synthesis. Thus far only pol α and pol δ have been implicated in the DNA replication of mammalian viruses; this is the first reported example of a virus recruiting pol ϵ. Furthermore, this demonstrates a unique capacity of a viral helicase having evolved to stimulate a cellular replicative DNA polymerase.

中文翻译:

人类乳头瘤病毒DNA解旋酶E1与细胞DNA聚合酶epsilon结合,刺激并赋予合成能力

乳头瘤病毒(PV)解旋酶蛋白E1将细胞DNA复制机制的组成部分募集到PV复制叉中,例如复制蛋白A(RPA),DNA聚合酶α-primase(polα)和拓扑异构酶I(拓扑I)。在这里,我们显示E1与DNA聚合酶ϵ(pol ϵ)结合并显着刺激pol ϵ的DNA合成活性。E1对pol ϵ的刺激是高度特异性的,即使在没有已知的pol ϵ辅助因子复制因子C(RFC),增殖细胞核抗原(PCNA)和RPA的情况下也是如此。这种刺激是由于pol的持续合成能力的提高引起的,并且独立于pol co的复制辅助因子而发生。持续性的提高取决于E1解旋酶水解ATP的能力,表明它依赖于E1解旋酶的作用。此外,RPA,被认为对pol ϵ和polδ进行DNA合成至关重要的分子,发现在E1存在下对于pol process进行DNA合成至关重要。总体而言,E1似乎通过将pol ϵ直接束缚在DNA亲本链上并随着复制叉的进行拖曳拖曳到E1解旋酶后面而赋予pol process合成能力。因此,显然消除了前导链合成对RPA的需要。到目前为止,只有polα和polδ参与了哺乳动物病毒的DNA复制。这是第一个报告的病毒募集策略。此外,这表明病毒解旋酶已经发展出刺激细胞复制性DNA聚合酶的独特能力。总体而言,E1似乎通过将pol ϵ直接束缚在DNA亲本链上并随着复制叉的进行拖曳拖曳到E1解旋酶后面而赋予pol process合成能力。因此,显然消除了前导链合成对RPA的需要。到目前为止,只有polα和polδ参与了哺乳动物病毒的DNA复制。这是第一个报告的病毒募集策略。此外,这表明病毒解旋酶已经发展出刺激细胞复制性DNA聚合酶的独特能力。总体而言,E1似乎通过将pol ϵ直接束缚在DNA亲本链上并随着复制叉的进行拖曳拖曳到E1解旋酶后面而赋予pol process合成能力。因此,显然消除了前导链合成对RPA的需要。到目前为止,只有polα和polδ参与了哺乳动物病毒的DNA复制。这是第一个报告的病毒募集策略。此外,这表明病毒解旋酶已经发展出刺激细胞复制性DNA聚合酶的独特能力。到目前为止,只有polα和polδ参与了哺乳动物病毒的DNA复制。这是第一个报告的病毒募集策略。此外,这表明病毒解旋酶已经发展出刺激细胞复制性DNA聚合酶的独特能力。到目前为止,只有polα和polδ参与了哺乳动物病毒的DNA复制。这是第一个报告的病毒募集策略。此外,这表明病毒解旋酶已经发展出刺激细胞复制性DNA聚合酶的独特能力。
更新日期:2017-11-16
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