The mitotic ATR-Chk1 pathway promotes CDK1 activity for faithful chromosome segregation
Yoon Ki Joo1, Carlos Ramirez Parrado1, Wenxue Li2
1Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT, USA.
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.
Insights
The ATR-Chk1 pathway maintains CDK1 activity during mitosis, ensuring faithful chromosome segregation. This contrasts its interphase role, highlighting a crucial, mitosis-specific function for DNA damage response kinases.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- The DNA damage response (DDR) pathway involves critical kinases like ATR and Chk1.
- While ATR and Chk1 roles in DDR are known, their function during mitosis remains unclear.
Purpose of the Study:
- To investigate the role of the ATR-Chk1 pathway in mitosis.
- To understand how ATR-Chk1 influences CDK1 activity and mitotic progression in human cells.
Main Methods:
- Investigated ATR-Chk1 pathway activity during mitosis.
- Analyzed Chk1 phosphorylation of PKMYT1 (Myt1) at Serine 143.
- Assessed the impact of Chk1 inhibition on CDK1 activity and mitotic progression, including chromosome segregation and Aurora B activity.
Main Results:
- The ATR-Chk1 pathway is rewired in mitosis to promote CDK1 activity, unlike its interphase function.
- Mitotic Chk1 directly phosphorylates and inhibits Myt1 at Serine 143.
- Partial loss of CDK1 activity due to Chk1 inhibition causes lagging chromosomes and reduced Aurora B activity.
Conclusions:
- Mitosis-specific ATR-Chk1 activity is essential for maintaining CDK1 activity.
- This maintenance of CDK1 activity by ATR-Chk1 is critical for faithful chromosome segregation during mitosis.
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