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.

中文翻译：

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Treacle 和 TOPBP1 控制核仁中的复制应激反应

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应激反应已被广泛研究，但对核仁中的复制应激反应几乎一无所知。在这里，我们证明了初始复制应激反应因子，如 RPA、TOPBP1 和 ATR，在核仁内被招募以响应药物诱导的复制应激。TOPBP1 的作用超出了典型的复制应激反应；它与低复杂性核仁蛋白 Treacle（也称为 TCOF1）相互作用，并在核仁内形成大的 Treacle-TOPBP1 焦点。为了响应复制应激，Treacle 和 TOPBP1 促进停滞复制叉处的 ATR 信号传导，增强核仁内 ATR 介导的检查点激活，并促进核仁内下游复制应激反应蛋白的募集，而不形成核仁帽。Treacle-TOPBP1 相互作用模式的表征使我们提出，这些因子可以形成核仁中有效应激反应的分子平台。