Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation
Tingjun Lei1, Peixuan Zhang1, Xudong Zhang1
1Department of Obstetrics and Gynecology, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, College of Life Sciences, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, 610041, Chengdu, China.
Nature Communications
|May 16, 2018
Summary
Cyclin K controls prereplicative complex (pre-RC) assembly in G1 phase, crucial for cell proliferation and genomic stability. It restricts cyclin E1 activity, preventing pre-RC formation in G1 and impacting tumorigenesis.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Prereplicative complex (pre-RC) assembly in G1 is vital for cell proliferation and genomic stability.
- Mechanisms preventing pre-RC formation in G2/M and S phases are known, but G1 assembly regulation is less understood.
Purpose of the Study:
- To investigate the role of cyclin K in regulating pre-RC assembly during the G1 phase.
- To elucidate the molecular mechanisms by which cyclin K controls pre-RC formation.
Main Methods:
- Correlation analysis of cyclin K expression with cell proliferation.
- Knockdown studies of cyclin K and CDK12 to assess pre-RC assembly.
- Identification of cyclin K-dependent phosphorylation sites on cyclin E1 using biochemical assays.
Main Results:
- Cyclin K expression positively correlates with cell proliferation.
- Knockdown of cyclin K or CDK12 inhibits pre-RC assembly in G1.
- Cyclin K phosphorylates cyclin E1 at a novel site, disrupting its interaction with CDK2.
- This regulatory mechanism is observed in cyclin E1-overexpressing tumors.
Conclusions:
- Cyclin K is a key regulator of pre-RC assembly in G1 phase.
- Cyclin K antagonizes cyclin E1 activity to ensure proper pre-RC formation.
- Dysregulation of this pathway may contribute to human tumorigenesis, highlighting cyclin K and CDK12 as potential therapeutic targets.
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