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CHK2 kinase promotes pre-mRNA splicing via phosphorylating CDK11(p110)

H-H Choi1, H-K Choi1, S Y Jung2

  • 1Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Republic of Korea.

Oncogene
|November 27, 2012
PubMed

Insights

Checkpoint kinase 2 (CHK2) promotes pre-mRNA splicing by phosphorylating cyclin-dependent kinase 11 (CDK11). This DNA damage-independent mechanism highlights a novel role for CHK2 in gene expression regulation.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • Checkpoint kinase 2 (CHK2) is a critical mediator of cellular responses to genotoxic stress, regulating cell cycle checkpoints, apoptosis, and DNA repair.
  • CHK2 is activated by ataxia telangiectasia mutated (ATM) kinase and phosphorylates targets like p53 and Brca1.
  • CHK2 is recognized as a potential multi-organ cancer susceptibility gene.

Purpose of the Study:

  • To identify proteins interacting with CHK2 kinase using a tandem affinity purification strategy.
  • To investigate the functional relationship between CHK2 and its interacting partners in cellular processes.
  • To elucidate the role of CHK2 in pre-mRNA splicing regulation.

Main Methods:

  • Tandem affinity purification to identify CHK2-interacting proteins.
  • In vitro kinase assays to determine phosphorylation sites and effects.
  • Overexpression and depletion studies to assess functional consequences.
  • Site-directed mutagenesis to investigate the role of specific phosphorylation sites.

Main Results:

  • Cyclin-dependent kinase 11 (CDK11)(p110) was identified as a novel CHK2-interacting protein.
  • CHK2 phosphorylates CDK11(p110) at serine 737 in a DNA damage-independent manner.
  • CDK11(p110) phosphorylation by CHK2 is essential for its homodimerization but not its kinase activity.
  • CHK2 overexpression enhances pre-mRNA splicing, while CHK2 depletion reduces it.
  • Mutation of the CDK11(p110) phosphorylation site abrogates its splicing-promoting activity.

Conclusions:

  • CHK2 kinase promotes pre-mRNA splicing through the phosphorylation of CDK11(p110).
  • This study reveals a novel function of CHK2 in regulating gene expression via the splicing machinery.
  • The findings provide new insights into the multifaceted roles of CHK2 beyond DNA damage response.

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