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周期蛋白依赖性激酶对 Treslin 的直接调控对于 DNA 复制的起始是必不可少的。

Direct regulation of Treslin by cyclin-dependent kinase is essential for the onset of DNA replication.

机构信息

Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.

出版信息

J Cell Biol. 2011 Jun 13;193(6):995-1007. doi: 10.1083/jcb.201102003. Epub 2011 Jun 6.

DOI:10.1083/jcb.201102003
PMID:21646402
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3115804/
Abstract

Treslin, a TopBP1-interacting protein, is necessary for deoxyribonucleic acid (DNA) replication in vertebrates. Association between Treslin and TopBP1 requires cyclin-dependent kinase (Cdk) activity in Xenopus laevis egg extracts. We investigated the mechanism and functional importance of Cdk for this interaction using both X. laevis egg extracts and human cells. We found that Treslin also associated with TopBP1 in a Cdk-regulated manner in human cells and that Treslin was phosphorylated within a conserved Cdk consensus target sequence (on S976 in X. laevis and S1000 in humans). Recombinant human Cdk2-cyclin E also phosphorylated this residue of Treslin in vitro very effectively. Moreover, a mutant of Treslin that cannot undergo phosphorylation on this site showed significantly diminished binding to TopBP1. Finally, human cells harboring this mutant were severely deficient in DNA replication. Collectively, these results indicate that Cdk-mediated phosphorylation of Treslin during S phase is necessary for both its effective association with TopBP1 and its ability to promote DNA replication in human cells.

摘要

Treslin 是与 TopBP1 相互作用的蛋白，在脊椎动物中对 DNA 复制是必需的。Treslin 与 TopBP1 的结合需要非洲爪蟾卵提取物中环依赖激酶（Cdk）的活性。我们使用非洲爪蟾卵提取物和人细胞研究了 Cdk 对这种相互作用的机制和功能重要性。我们发现 Treslin 也以 Cdk 调节的方式与人细胞中的 TopBP1 相关联，并且 Treslin 在保守的 Cdk 一致靶序列内（在非洲爪蟾的 S976 和人类的 S1000 上）被磷酸化。重组人 Cdk2-细胞周期蛋白 E 也非常有效地在体外磷酸化 Treslin 的这个残基。此外，该位点不能发生磷酸化的 Treslin 突变体与 TopBP1 的结合显著减少。最后，携带该突变体的人细胞在 DNA 复制中严重缺乏。总之，这些结果表明，在 S 期 Cdk 介导的 Treslin 磷酸化对于 Treslin 与 TopBP1 的有效结合及其在人细胞中促进 DNA 复制的能力都是必需的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/afb5d08d18df/JCB_201102003_GS_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/5dad1f049939/JCB_201102003_GS_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/00b76dec26c4/JCB_201102003_RGB_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/d06a66e770d5/JCB_201102003_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/2d32fbc854d8/JCB_201102003_GS_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/3738d5b6383c/JCB_201102003_GS_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/1eef7ef05979/JCB_201102003_RGB_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/3383b803b097/JCB_201102003_RGB_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/afb5d08d18df/JCB_201102003_GS_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/5dad1f049939/JCB_201102003_GS_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/00b76dec26c4/JCB_201102003_RGB_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/d06a66e770d5/JCB_201102003_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/2d32fbc854d8/JCB_201102003_GS_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/3738d5b6383c/JCB_201102003_GS_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/1eef7ef05979/JCB_201102003_RGB_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/3383b803b097/JCB_201102003_RGB_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dfe7/3115804/afb5d08d18df/JCB_201102003_GS_Fig8.jpg

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