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糖蜜和 TOPBP1 控制核仁中的复制应激反应。

Treacle and TOPBP1 control replication stress response in the nucleolus.

机构信息

Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.

Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Institute of Gene Biology Russian Academy of Sciences, Moscow, Russia.

出版信息

J Cell Biol. 2021 Aug 2;220(8). doi: 10.1083/jcb.202008085. Epub 2021 Jun 8.

DOI:10.1083/jcb.202008085
PMID:34100862
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8190600/
Abstract

Replication stress is one of the main sources of genome instability. Although the replication stress response in eukaryotic cells has been extensively studied, almost nothing is known about the replication stress response in nucleoli. Here, we demonstrate that initial replication stress-response factors, such as RPA, TOPBP1, and ATR, are recruited inside the nucleolus in response to drug-induced replication stress. The role of TOPBP1 goes beyond the typical replication stress response; it interacts with the low-complexity nucleolar protein Treacle (also referred to as TCOF1) and forms large Treacle-TOPBP1 foci inside the nucleolus. In response to replication stress, Treacle and TOPBP1 facilitate ATR signaling at stalled replication forks, reinforce ATR-mediated checkpoint activation inside the nucleolus, and promote the recruitment of downstream replication stress response proteins inside the nucleolus without forming nucleolar caps. Characterization of the Treacle-TOPBP1 interaction mode leads us to propose that these factors can form a molecular platform for efficient stress response in the nucleolus.

摘要

复制压力是基因组不稳定的主要来源之一。尽管真核细胞中的复制压力反应已经得到了广泛的研究，但几乎不知道核仁中的复制压力反应。在这里，我们证明了初始复制压力反应因子，如 RPA、TOPBP1 和 ATR，会被招募到核仁内，以响应药物诱导的复制压力。TOPBP1 的作用超出了典型的复制压力反应；它与低复杂度核仁蛋白 Treacle（也称为 TCOF1）相互作用，并在核仁内形成大的 Treacle-TOPBP1 焦点。在复制压力下，Treacle 和 TOPBP1 促进停滞复制叉处的 ATR 信号转导，增强核仁内 ATR 介导的检查点激活，并促进下游复制压力反应蛋白在核仁内的招募，而不会形成核仁帽。Treacle-TOPBP1 相互作用模式的表征使我们提出这些因素可以形成核仁中有效应激反应的分子平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8190600/aa79d3b31291/JCB_202008085_Fig8.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/dd5c/8190600/6c40480e6d85/JCB_202008085_FigS1.jpg
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