有丝分裂期的ATR-Chk1信号通路促进CDK1活性，以确保染色体的准确分离。
The mitotic ATR-Chk1 pathway promotes CDK1 activity for faithful chromosome segregation.
作者信息
Joo Yoon Ki, Parrado Carlos Ramirez, Li Wenxue, Yang Ran, Black Elizabeth, Bleichert Franziska, Liu Yansheng, Kabeche Lilian
机构信息
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
Yale Cancer Biology Institute, Yale University, West Haven, CT, USA; Department of Pharmacology, Yale University, New Haven, CT, USA.
出版信息
Cell Rep. 2025 Aug 26;44(8):116019. doi: 10.1016/j.celrep.2025.116019. Epub 2025 Jul 23.
Ataxia telangiectasia and Rad3-related (ATR) and checkpoint kinase 1 (Chk1) are crucial kinases in the DNA damage response (DDR) pathway. While the roles of ATR and Chk1 within the DDR are well established, their roles in mitosis are not fully understood. Here, we describe that the ATR-Chk1 pathway is rewired during mitosis to promote full CDK1 activity, starkly contrasting its role in interphase, where it inhibits CDK1 following DNA damage in human cells. In mitosis, Chk1 inhibits residual activity of PKMYT1 (Myt1) via direct phosphorylation at Serine 143. Partial loss of CDK1 activity caused by inhibition of mitotic Chk1 leads to different effects on mitotic progression than full CDK1 inhibition. It causes increased lagging chromosomes in part through loss of Aurora B activity. Thus, mitosis-specific ATR-Chk1 activity is necessary to promote faithful chromosome segregation by ensuring that CDK1 activity is maintained in mitosis.
共济失调毛细血管扩张症突变蛋白和Rad3相关蛋白（ATR）以及检查点激酶1（Chk1）是DNA损伤反应（DDR）途径中的关键激酶。虽然atr和Chk在DDR中的作用已得到充分证实，不过它们在有丝分裂中的作用尚未完全明确。在此，我们描述在有丝分裂过程中ATR-Chk1途径会被重新布线以促进CDK1的完全活性，这与它在间期的作用形成鲜明对比，在间期，它在人类细胞DNA损伤后抑制CDK1。在有丝分裂中，Chk1通过直接磷酸化丝氨酸143来抑制PKMYT1（Myt1）的残余活性。与完全抑制CDK1相比，有丝分裂期Chk1抑制导致的CDK1活性部分丧失对有丝分裂进程产生不同影响。它部分通过Aurora B活性丧失导致滞后染色体增加。因此，有丝分裂特异性ATR-Chk1活性对于通过确保有丝分裂中CDK1活性得以维持来促进染色体正确分离是必要的。
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