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单分子成像揭示了原生动物中双向复制起始的机制。

Single-molecule imaging reveals the mechanism of bidirectional replication initiation in metazoa.

机构信息

Chemical and Systems Biology Department, Stanford School of Medicine, Stanford, CA 94305, USA.

Biophysics Program, Stanford School of Medicine, Stanford, CA 94305, USA.

出版信息

Cell. 2024 Jul 25;187(15):3992-4009.e25. doi: 10.1016/j.cell.2024.05.024. Epub 2024 Jun 11.

DOI:10.1016/j.cell.2024.05.024
PMID:38866019
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11283366/
Abstract

Metazoan genomes are copied bidirectionally from thousands of replication origins. Replication initiation entails the assembly and activation of two CMG helicases (Cdc45⋅Mcm2-7⋅GINS) at each origin. This requires several replication firing factors (including TopBP1, RecQL4, and DONSON) whose exact roles are still under debate. How two helicases are correctly assembled and activated at each origin is a long-standing question. By visualizing the recruitment of GINS, Cdc45, TopBP1, RecQL4, and DONSON in real time, we uncovered that replication initiation is surprisingly dynamic. First, TopBP1 transiently binds to the origin and dissociates before the start of DNA synthesis. Second, two Cdc45 are recruited together, even though Cdc45 alone cannot dimerize. Next, two copies of DONSON and two GINS simultaneously arrive at the origin, completing the assembly of two CMG helicases. Finally, RecQL4 is recruited to the CMG⋅DONSON⋅DONSON⋅CMG complex and promotes DONSON dissociation and CMG activation via its ATPase activity.

摘要

后生动物基因组从数千个复制起点双向复制。复制起始需要在每个起点组装和激活两个 CMG 解旋酶（Cdc45⋅Mcm2-7⋅GINS）。这需要几个复制引发因子（包括 TopBP1、RecQL4 和 DONSON），其确切作用仍在争论中。两个解旋酶如何在每个起点正确组装和激活是一个长期存在的问题。通过实时可视化 GINS、Cdc45、TopBP1、RecQL4 和 DONSON 的募集，我们发现复制起始出乎意料地具有动态性。首先，TopBP1 短暂地结合到原点上，并在 DNA 合成开始之前解离。其次，两个 Cdc45 一起被招募，尽管 Cdc45 本身不能二聚化。接下来，两个 DONSON 和两个 GINS 同时到达原点，完成两个 CMG 解旋酶的组装。最后，RecQL4 被招募到 CMG⋅DONSON⋅DONSON⋅CMG 复合物上，并通过其 ATP 酶活性促进 DONSON 解离和 CMG 激活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/a46101f87a5e/nihms-2003547-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/76a12bfecff9/nihms-2003547-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/776273363e61/nihms-2003547-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/775e5cd4ac23/nihms-2003547-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/5156f911b9f1/nihms-2003547-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/56a2c9a046ea/nihms-2003547-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/56a1755c08a5/nihms-2003547-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/a46101f87a5e/nihms-2003547-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/76a12bfecff9/nihms-2003547-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/776273363e61/nihms-2003547-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/775e5cd4ac23/nihms-2003547-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/5156f911b9f1/nihms-2003547-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/56a2c9a046ea/nihms-2003547-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/56a1755c08a5/nihms-2003547-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98ea/11283366/a46101f87a5e/nihms-2003547-f0007.jpg

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Nat Commun. 2024 Feb 27;15(1):1797. doi: 10.1038/s41467-024-45946-0.
3
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Nat Commun. 2025 May 3;16(1):4140. doi: 10.1038/s41467-025-59509-4.
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