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T抗原与复制蛋白A对DNA聚合酶α-引发酶启动DNA合成的影响。

Effects of T antigen and replication protein A on the initiation of DNA synthesis by DNA polymerase alpha-primase.

作者信息

Collins K L, Kelly T J

机构信息

Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.

出版信息

Mol Cell Biol. 1991 Apr;11(4):2108-15. doi: 10.1128/mcb.11.4.2108-2115.1991.

DOI:10.1128/mcb.11.4.2108-2115.1991
PMID:1848671
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC359898/
Abstract

Studies of simian virus 40 (SV40) DNA replication in a reconstituted cell-free system have established that T antigen and two cellular replication proteins, replication protein A (RP-A) and DNA polymerase alpha-primase complex, are necessary and sufficient for initiation of DNA synthesis on duplex templates containing the SV40 origin of DNA replication. To better understand the mechanism of initiation of DNA synthesis, we analyzed the functional interactions of T antigen, RP-A, and DNA polymerase alpha-primase on model single-stranded DNA templates. Purified DNA polymerase alpha-primase was capable of initiating DNA synthesis de novo on unprimed single-stranded DNA templates. This reaction involved the synthesis of a short oligoribonucleotide primer which was then extended into a DNA chain. We observed that the synthesis of ribonucleotide primers by DNA polymerase alpha-primase is dramatically stimulated by SV40 T antigen. The presence of T antigen also increased the average length of the DNA product synthesized on primed and unprimed single-stranded DNA templates. These stimulatory effects of T antigen required direct contact with DNA polymerase alpha-primase complex and were most marked at low template and polymerase concentrations. We also observed that the single-stranded DNA binding protein, RP-A, strongly inhibits the primase activity of DNA polymerase alpha-primase, probably by blocking access of the enzyme to the template. T antigen partially reversed the inhibition caused by RP-A. Our data support a model in which DNA priming is mediated by a complex between T antigen and DNA polymerase alpha-primase with the template, while RP-A acts to suppress nonspecific priming events.

摘要

在一个重组的无细胞系统中对猿猴病毒40（SV40）DNA复制进行的研究表明，T抗原以及两种细胞复制蛋白，即复制蛋白A（RP-A）和DNA聚合酶α-引发酶复合物，对于在含有SV40 DNA复制起点的双链模板上启动DNA合成是必要且充分的。为了更好地理解DNA合成起始的机制，我们分析了T抗原、RP-A和DNA聚合酶α-引发酶在模型单链DNA模板上的功能相互作用。纯化的DNA聚合酶α-引发酶能够在未引发的单链DNA模板上从头启动DNA合成。该反应涉及短寡核糖核苷酸引物的合成，然后将其延伸成DNA链。我们观察到，SV40 T抗原能显著刺激DNA聚合酶α-引发酶合成核糖核苷酸引物。T抗原的存在还增加了在引发和未引发的单链DNA模板上合成的DNA产物的平均长度。T抗原的这些刺激作用需要与DNA聚合酶α-引发酶复合物直接接触，并且在低模板和聚合酶浓度下最为明显。我们还观察到，单链DNA结合蛋白RP-A强烈抑制DNA聚合酶α-引发酶的引发酶活性，可能是通过阻止该酶与模板的接触。T抗原部分逆转了RP-A引起的抑制作用。我们的数据支持这样一个模型：DNA引发是由T抗原与DNA聚合酶α-引发酶和模板之间的复合物介导的，而RP-A则起到抑制非特异性引发事件的作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/a3465d7185dd/molcellb00138-0348-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/44b36367eb95/molcellb00138-0345-a.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/a3465d7185dd/molcellb00138-0348-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/44b36367eb95/molcellb00138-0345-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/b3e1a1b5108d/molcellb00138-0346-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/cf748165de32/molcellb00138-0346-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/e5a148e30dfe/molcellb00138-0347-a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/7060c58cd3b1/molcellb00138-0347-b.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/ac1c785967b2/molcellb00138-0347-c.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2b69/359898/a3465d7185dd/molcellb00138-0348-a.jpg

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