Wan Bingbing, Guan Danying, Li Shibai, Chwat-Edelstein Tzippora, Zhao Xiaolan
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Commun. 2025 Jan 2;16(1):311. doi: 10.1038/s41467-024-54624-0.
The DNA damage checkpoint is a highly conserved signaling pathway induced by genotoxin exposure or endogenous genome stress. It alters many cellular processes such as arresting the cell cycle progression and increasing DNA repair capacities. However, cells can downregulate the checkpoint after prolonged stress exposure to allow continued growth and alternative repair. Strategies that can dampen the DNA damage checkpoint are not well understood. Here, we report that budding yeast employs a pathway composed of the scaffold protein Rtt107, its binding partner Mms22, and an Mms22-associated ubiquitin ligase complex to downregulate the DNA damage checkpoint. Mechanistically, this pathway promotes the proteasomal degradation of a key checkpoint factor, Rad9. Furthermore, Rtt107 binding to Mms22 helps to enrich the ubiquitin ligase complex on chromatin for targeting the chromatin-bound form of Rad9. Finally, we provide evidence that the Rtt107-Mms22 axis operates in parallel with the Rtt107-Slx4 axis, which displaces Rad9 from chromatin. We thus propose that Rtt107 enables a bifurcated "anti-Rad9" strategy to optimally downregulate the DNA damage checkpoint.
DNA损伤检查点是一种由基因毒素暴露或内源性基因组应激诱导的高度保守的信号通路。它会改变许多细胞过程，如阻止细胞周期进程和提高DNA修复能力。然而，在长时间应激暴露后，细胞可以下调检查点，以允许持续生长和进行替代修复。能够抑制DNA损伤检查点的策略目前还不太清楚。在这里，我们报告出芽酵母利用一条由支架蛋白Rtt107、其结合伴侣Mms22以及一个与Mms22相关的泛素连接酶复合物组成的通路来下调DNA损伤检查点。从机制上讲，这条通路促进了关键检查点因子Rad9的蛋白酶体降解。此外，Rtt107与Mms22的结合有助于在染色质上富集泛素连接酶复合物，以靶向染色质结合形式的Rad9。最后，我们提供证据表明Rtt107-Mms22轴与Rtt107-Slx4轴并行运作，后者将Rad9从染色质上置换下来。因此，我们提出Rtt107启用了一种分叉的“抗Rad9”策略，以最佳方式下调DNA损伤检查点。
