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MCM8/9 解旋酶复合物在复制应激过程中维持叉完整性的多功能作用。

A multi-functional role for the MCM8/9 helicase complex in maintaining fork integrity during replication stress.

机构信息

Department of Chemistry and Biochemistry, Baylor University, Waco, TX, 76706, USA.

St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.

出版信息

Nat Commun. 2022 Aug 30;13(1):5090. doi: 10.1038/s41467-022-32583-8.

DOI:10.1038/s41467-022-32583-8
PMID:36042199
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9427862/
Abstract

The minichromosome maintenance (MCM) 8/9 helicase is a AAA complex involved in DNA replication-associated repair. Despite high sequence homology to the MCM2-7 helicase, a precise cellular role for MCM8/9 has remained elusive. We have interrogated the DNA synthesis ability and replication fork stability in cells lacking MCM8 or 9 and find that there is a functional partitioning of MCM8/9 activity between promoting replication fork progression and protecting persistently stalled forks. The helicase function of MCM8/9 aids in normal replication fork progression, but upon persistent stalling, MCM8/9 directs additional downstream stabilizers, including BRCA1 and Rad51, to protect forks from excessive degradation. Loss of MCM8 or 9 slows the overall replication rate and allows for excessive nascent strand degradation, detectable by increased markers of genomic damage. This evidence defines multifunctional roles for MCM8/9 in promoting normal replication fork progression and genome integrity following stress.

摘要

微小染色体维持（MCM）8/9 解旋酶是一种参与 DNA 复制相关修复的 AAA 复合物。尽管与 MCM2-7 解旋酶具有高度的序列同源性，但 MCM8/9 的精确细胞作用仍然难以捉摸。我们研究了缺乏 MCM8 或 9 的细胞的 DNA 合成能力和复制叉稳定性，发现 MCM8/9 活性在促进复制叉进展和保护持续停滞的叉之间存在功能分区。MCM8/9 的解旋酶功能有助于正常的复制叉进展，但在持续停滞时，MCM8/9 将其他下游稳定剂，包括 BRCA1 和 Rad51，引导到叉上，以防止过度降解。MCM8 或 9 的缺失会降低整体复制速度，并允许过多的新生链降解，这可以通过增加基因组损伤的标志物来检测到。这一证据定义了 MCM8/9 在促进正常复制叉进展和压力后基因组完整性方面的多功能作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/3662caf2c088/41467_2022_32583_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/c5359d95eb6d/41467_2022_32583_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/995f13f5cd3b/41467_2022_32583_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/49531b861944/41467_2022_32583_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/9f3228125a4c/41467_2022_32583_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/509fc5d44446/41467_2022_32583_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/35984d18933e/41467_2022_32583_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/da0cc22db6a2/41467_2022_32583_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/3662caf2c088/41467_2022_32583_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/c5359d95eb6d/41467_2022_32583_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/995f13f5cd3b/41467_2022_32583_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/49531b861944/41467_2022_32583_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/9f3228125a4c/41467_2022_32583_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/509fc5d44446/41467_2022_32583_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/35984d18933e/41467_2022_32583_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/da0cc22db6a2/41467_2022_32583_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ff2e/9427862/3662caf2c088/41467_2022_32583_Fig8_HTML.jpg

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