2. Academic Validation
  3. The mitotic ATR-Chk1 pathway promotes CDK1 activity for faithful chromosome segregation

The mitotic ATR-Chk1 pathway promotes CDK1 activity for faithful chromosome segregation

  • Cell Rep. 2025 Aug 26;44(8):116019. doi: 10.1016/j.celrep.2025.116019.
Yoon Ki Joo 1,  Carlos Ramirez Parrado 1,  Wenxue Li 2,  Ran Yang 3,  Elizabeth Black 1,  Franziska Bleichert 3,  Yansheng Liu 4,  Lilian Kabeche 5
Affiliations

Affiliations

  • 1 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
  • 2 Yale Cancer Biology Institute, Yale University, West Haven, CT, USA; Department of Pharmacology, Yale University, New Haven, CT, USA.
  • 3 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
  • 4 Yale Cancer Biology Institute, Yale University, West Haven, CT, USA; Department of Pharmacology, Yale University, New Haven, CT, USA; Department of Biomedical Informatics & Data Science, Yale University, New Haven, CT, USA.
  • 5 Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA. Electronic address: lilian.kabeche@yale.edu.
PMID: 40705605 DOI: 10.1016/j.celrep.2025.116019
Abstract

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.

Keywords

ATR; CDK1; CP: Molecular biology; Chk1; DNA damage response pathway; cell cycle; chromosome segregation; mitosis.

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