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接近停滞的DNA复制叉处的转录引发核糖体DNA拷贝数变化。

Transcription near arrested DNA replication forks triggers ribosomal DNA copy number changes.

作者信息

Sasaki Mariko, Kobayashi Takehiko

机构信息

Laboratory of Gene Quantity Biology, Center for Frontier Research, National Institute of Genetics, 1111 Yata, Mishima, Shizuoka411-8540, Japan.

The Graduate University for Advanced Studies, SOKENDAI, 1111 Yata, Mishima, Shizuoka411-8540, Japan.

出版信息

Nucleic Acids Res. 2025 Jan 24;53(3). doi: 10.1093/nar/gkaf014.

DOI:10.1093/nar/gkaf014
PMID:39876709
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11760980/
Abstract

DNA copy number changes via chromosomal rearrangements or the production of extrachromosomal circular DNA. Here, we demonstrate that the histone deacetylase Sir2 maintains the copy number of budding yeast ribosomal RNA gene [ribosomal DNA (rDNA)] by suppressing end resection of DNA double-strand breaks (DSBs) formed upon DNA replication fork arrest in the rDNA and their subsequent homologous recombination (HR)-mediated rDNA copy number changes during DSB repair. Sir2 represses transcription from the regulatory promoter E-pro located near the fork arresting site. When Sir2 is absent, this transcription is stimulated but terminated by arrested replication forks. This transcription-replication collision induces DSB formation, DSB end resection and the Mre11-Rad50-Xrs2 complex-dependent DSB repair that is prone to chromosomal rDNA copy number changes and the production of extrachromosomal rDNA circles. Therefore, repression of transcription near arrested replication forks is critical for the maintenance of rDNA stability by directing DSB repair into the HR-independent, rearrangement-free pathway.

摘要

DNA拷贝数通过染色体重排或染色体外环状DNA的产生而发生变化。在此，我们证明组蛋白去乙酰化酶Sir2通过抑制在核糖体DNA（rDNA）中DNA复制叉停滞时形成的DNA双链断裂（DSB）的末端切除以及随后在DSB修复过程中同源重组（HR）介导的rDNA拷贝数变化，来维持芽殖酵母核糖体RNA基因[rDNA]的拷贝数。Sir2抑制位于复制叉停滞位点附近的调控启动子E-pro的转录。当Sir2缺失时，这种转录会被刺激，但会被停滞的复制叉终止。这种转录-复制碰撞会诱导DSB的形成、DSB末端切除以及依赖于Mre11-Rad50-Xrs2复合物的DSB修复，而这种修复容易导致染色体rDNA拷贝数变化和染色体外rDNA环的产生。因此，抑制停滞复制叉附近的转录对于通过将DSB修复导向不依赖HR、无重排的途径来维持rDNA稳定性至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/c78d961d82ba/gkaf014fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/f7c69dbd07dc/gkaf014figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/8932150e26bf/gkaf014fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/efd9b91058e6/gkaf014fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/019bf0b2a91c/gkaf014fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/2c40859c9530/gkaf014fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/1b2e9ba4f4ae/gkaf014fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/d603ba38124b/gkaf014fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/c78d961d82ba/gkaf014fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/f7c69dbd07dc/gkaf014figgra1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/8932150e26bf/gkaf014fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/efd9b91058e6/gkaf014fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/019bf0b2a91c/gkaf014fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/2c40859c9530/gkaf014fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/1b2e9ba4f4ae/gkaf014fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/d603ba38124b/gkaf014fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26c2/11760980/c78d961d82ba/gkaf014fig7.jpg

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本文引用的文献

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Mol Cell. 2025 Jan 2;85(1):61-77.e6. doi: 10.1016/j.molcel.2024.10.032. Epub 2024 Dec 3.
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Transcription-Replication Conflicts as a Source of Genome Instability.转录-复制冲突作为基因组不稳定性的一个来源。
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Spt4 promotes cellular senescence by activating non-coding RNA transcription in ribosomal RNA gene clusters.Spt4 通过激活核糖体 RNA 基因簇中的非编码 RNA 转录促进细胞衰老。
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