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CMG 解旋酶的解体由复制叉 DNA、复制体组件和泛素阈值控制。

CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold.

机构信息

The MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, United Kingdom.

出版信息

Elife. 2020 Aug 17;9:e60371. doi: 10.7554/eLife.60371.

DOI:10.7554/eLife.60371
PMID:32804080
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7462611/
Abstract

The eukaryotic replisome assembles around the CMG helicase, which stably associates with DNA replication forks throughout elongation. When replication terminates, CMG is ubiquitylated on its Mcm7 subunit and disassembled by the Cdc48/p97 ATPase. Until now, the regulation that restricts CMG ubiquitylation to termination was unknown, as was the mechanism of disassembly. By reconstituting these processes with purified budding yeast proteins, we show that ubiquitylation is tightly repressed throughout elongation by the Y-shaped DNA structure of replication forks. Termination removes the repressive DNA structure, whereupon long K48-linked ubiquitin chains are conjugated to CMG-Mcm7, dependent on multiple replisome components that bind to the ubiquitin ligase SCF. This mechanism pushes CMG beyond a '5-ubiquitin threshold' that is inherent to Cdc48, which specifically unfolds ubiquitylated Mcm7 and thereby disassembles CMG. These findings explain the exquisite regulation of CMG disassembly and provide a general model for the disassembly of ubiquitylated protein complexes by Cdc48.

摘要

真核复制体围绕着 CMG 解旋酶组装，CMG 解旋酶在延伸过程中稳定地与 DNA 复制叉结合。当复制终止时，CMG 在其 Mcm7 亚基上被泛素化，并被 Cdc48/p97 ATP 酶解组装。直到现在，限制 CMG 泛素化仅限于终止的调节机制以及解组装的机制仍不清楚。通过用纯化的 budding yeast 蛋白重新构建这些过程，我们表明，在延伸过程中，Y 型 DNA 结构的复制叉严格抑制泛素化。终止去除抑制性 DNA 结构，随后长 K48 连接的泛素链与 CMG-Mcm7 结合，这依赖于多个与泛素连接酶 SCF 结合的复制体成分。该机制将 CMG 推过 Cdc48 固有的“5-泛素阈值”，Cdc48 特异性展开泛素化的 Mcm7，从而解组装 CMG。这些发现解释了 CMG 解组装的精细调节，并为 Cdc48 解组装泛素化蛋白复合物提供了一个通用模型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/65bc7d4a98c4/elife-60371-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/c5804efd7d64/elife-60371-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/470c1103d1dd/elife-60371-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/7e2547c9bc01/elife-60371-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/1955ddd2a37b/elife-60371-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/15db40e549d6/elife-60371-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/23f147c29de6/elife-60371-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/ad704013f87e/elife-60371-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/b8f6909ed3bb/elife-60371-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/4aab771ffd4e/elife-60371-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/e4b6dd3314cb/elife-60371-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/b88c21c47d77/elife-60371-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/80317818b175/elife-60371-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/0311ea6ab28d/elife-60371-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/65bc7d4a98c4/elife-60371-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/c5804efd7d64/elife-60371-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/470c1103d1dd/elife-60371-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/7e2547c9bc01/elife-60371-fig1-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/1955ddd2a37b/elife-60371-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/15db40e549d6/elife-60371-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/23f147c29de6/elife-60371-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/ad704013f87e/elife-60371-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/b8f6909ed3bb/elife-60371-fig3-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/4aab771ffd4e/elife-60371-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/e4b6dd3314cb/elife-60371-fig4-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/b88c21c47d77/elife-60371-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/80317818b175/elife-60371-fig5-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/0311ea6ab28d/elife-60371-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a72c/7462611/65bc7d4a98c4/elife-60371-fig6-figsupp1.jpg

相似文献

[1]
CMG helicase disassembly is controlled by replication fork DNA, replisome components and a ubiquitin threshold.

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[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[10]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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本文引用的文献

[1]
Cryo-EM Structure of the Fork Protection Complex Bound to CMG at a Replication Fork.

Mol Cell. 2020-6-4

[2]
In Vitro Reconstitution Defines the Minimal Requirements for Cdc48-Dependent Disassembly of the CMG Helicase in Budding Yeast.

Cell Rep. 2019-9-10

[3]
A conserved Mcm4 motif is required for Mcm2-7 double-hexamer formation and origin DNA unwinding.

Elife. 2019-8-6

[4]
Replication Fork Activation Is Enabled by a Single-Stranded DNA Gate in CMG Helicase.

Cell. 2019-7-25

[5]
Substrate processing by the Cdc48 ATPase complex is initiated by ubiquitin unfolding.

Science. 2019-6-27

[6]
Structure of the Cdc48 segregase in the act of unfolding an authentic substrate.

Science. 2019-6-27

[7]
Pif1-Family Helicases Support Fork Convergence during DNA Replication Termination in Eukaryotes.

Mol Cell. 2019-3-5

[8]
TRAIP is a master regulator of DNA interstrand crosslink repair.

Nature. 2019-3-6

[9]
To Build by Destruction.

Mol Cell. 2018-11-15

[10]
Ubiquitin-Independent Disassembly by a p97 AAA-ATPase Complex Drives PP1 Holoenzyme Formation.

Mol Cell. 2018-10-18

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