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CDK12 regulates co-transcriptional splicing and RNA turnover in human cells

Brian Magnuson1,2, Karan Bedi1,2, Ishwarya Venkata Narayanan3

  • 1Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.

Iscience
|September 16, 2022
PubMed

Insights

Cyclin-dependent kinase CDK12 inhibition impacts DNA repair and cell cycle genes by causing premature transcription termination. CDK12 loss also affects RNA turnover and splicing, crucial for DNA damage response gene expression.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Cyclin-dependent kinase CDK12 (CDK12) is a potential cancer therapeutic target.
  • Loss of CDK12 activity suppresses DNA damage response genes.

Purpose of the Study:

  • To investigate the acute effects of CDK12 inhibition on transcription and RNA processing.
  • To elucidate CDK12's roles in gene regulation.

Main Methods:

  • Nascent RNA sequencing (Bru-seq) and RNA decay analysis (BruChase-seq) were employed.
  • Acute CDK12 inhibition was induced to assess transcriptional and post-transcriptional changes.

Main Results:

  • CDK12 inhibition led to widespread intragenic premature termination in over 600 genes, including DNA repair and cell cycle genes.
  • Reduced transcriptional readthrough and significantly altered RNA turnover were observed.
  • Degradation of many DNA damage response gene transcripts increased upon CDK12 inhibition.
  • Co-transcriptional splicing was suppressed by CDK12 inhibition.

Conclusions:

  • CDK12 plays a critical role in regulating transcription elongation and termination.
  • CDK12 is essential for proper RNA turnover and co-transcriptional splicing.
  • These findings highlight CDK12's multifaceted role in gene expression, particularly impacting DNA damage response pathways.
Keywords:
Biological sciencescell biologymolecular biology

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