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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion

Jerry F Tien1, Alborz Mazloomian2,3, S-W Grace Cheng1

  • 1Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver V5Z 1L3, Canada.

Nucleic Acids Research
|March 24, 2017
PubMed

Insights

Cyclin-dependent kinase 12 (CDK12) primarily regulates alternative last exon splicing, impacting DNA repair and cell invasion in breast cancer. CDK12 amplification correlates with increased tumor cell migration and invasiveness, suggesting a role in cancer development.

Area of Science:

  • Molecular Biology
  • Cancer Genomics
  • Transcriptional Regulation

Background:

  • Cyclin-dependent kinase 12 (CDK12) is a regulatory kinase involved in transcription elongation.
  • Recurrent CDK12 mutations are found in breast and ovarian cancers, potentially disrupting DNA repair.
  • CDK12 is often co-amplified with the HER2 oncogene in breast cancers, but its precise functions remain unclear.

Purpose of the Study:

  • To investigate the mechanisms of CDK12 function in cancer.
  • To determine the role of CDK12 in breast cancer pathogenesis.
  • To analyze the impact of CDK12 amplification on mRNA splicing and tumor cell behavior.

Main Methods:

  • Global mRNA transcript analysis in normal and breast cancer cell lines.
  • Comparison of cell lines with and without CDK12 amplification.
  • Assessment of alternative last exon (ALE) splicing patterns.
  • Correlation analysis between CDK12 levels, DNAJB6 isoforms, and cell migration/invasion.

Main Results:

  • CDK12 primarily regulates gene- and cell type-specific alternative last exon (ALE) splicing.
  • CDK12 modulates ALE splicing of ATM and a DNAJB6 isoform in breast cancer cells.
  • CDK12 levels directly correlate with DNAJB6 isoform levels, cell migration, and invasiveness.

Conclusions:

  • CDK12's primary role is regulating specific ALE splicing events.
  • CDK12 amplification in breast cancer can contribute to pathogenesis by influencing DNA repair and cell invasion.
  • Targeting CDK12 may offer therapeutic strategies for breast cancer.

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