Identification PMS1 and PMS2 as potential meiotic substrates of CDK2 activity
Nathan Palmer1,2, S Zakiah A Talib1,3, Christine M F Goh1
1Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore, Republic of Singapore.
Abstract:
Cyclin dependent-kinase 2 (CDK2) plays important functions during the mitotic cell cycle and also facilitates several key events during germ cell development. The majority of CDK2's known meiotic functions occur during prophase of the first meiotic division. Here, CDK2 is involved in the regulation of meiotic transcription, the pairing of homologous chromosomes, and the maturation of meiotic crossover sites. Despite that some of the CDK2 substrates are known, few of them display functions in meiosis. Here, we investigate potential meiotic CDK2 substrates using in silico and in vitro approaches. We find that CDK2 phosphorylates PMS2 at Thr337, PMS1 at Thr331, and MLH1 in vitro. Phosphorylation of PMS2 affects its interaction with MLH1 to some degree. In testis extracts from mice lacking Cdk2, there are changes in expression of PMS2, MSH2, and HEI10, which may be reflective of the loss of CDK2 phosphorylation. Our work has uncovered a few CDK2 substrates with meiotic functions, which will have to be verified in vivo. A better understanding of the CDK2 substrates will help us to gain deeper insight into the functions of this universal kinase.
Insights
Cyclin-dependent kinase 2 (CDK2) phosphorylates key proteins like PMS2 during meiosis. This research identifies new CDK2 substrates involved in germ cell development, offering insights into kinase functions.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Cyclin-dependent kinase 2 (CDK2) is crucial for cell cycle progression and germ cell development.
- CDK2's meiotic roles, particularly in prophase I, involve regulating transcription, homologous chromosome pairing, and crossover maturation.
- While some CDK2 substrates are known, few have established meiotic functions.
Purpose of the Study:
- To identify and investigate novel meiotic substrates of CDK2.
- To explore the role of CDK2 phosphorylation in germ cell development and meiosis.
Main Methods:
- In silico and in vitro approaches were used to identify potential CDK2 substrates.
- In vitro kinase assays were performed to test phosphorylation of PMS2, PMS1, and MLH1 by CDK2.
- Analysis of mouse testis extracts lacking Cdk2 was conducted.
Main Results:
- CDK2 was found to phosphorylate PMS2 at Thr337, PMS1 at Thr331, and MLH1 in vitro.
- CDK2 phosphorylation of PMS2 showed a moderate impact on its interaction with MLH1.
- Absence of CDK2 in mice led to altered expression of PMS2, MSH2, and HEI10 in testis extracts.
Conclusions:
- This study identified PMS2, PMS1, and MLH1 as potential meiotic substrates of CDK2.
- The findings suggest CDK2 plays a role in regulating DNA repair proteins during meiosis.
- Further in vivo validation is required to confirm the meiotic functions of these newly identified CDK2 substrates.
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