CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

Area of Science:

• Molecular Biology
• Cancer Biology
• Genetics

Background:

• Cyclin-dependent kinase 12 (CDK12) is implicated in RNA polymerase II (RNAPII) elongation and is frequently altered in cancers.
• Previous studies suggest CDK12 depletion affects homologous recombination (HR) DNA repair gene expression, but its broader roles remain unclear.

Purpose of the Study:

• To investigate the function of CDK12 kinase activity in gene transcription and cellular processes using a chemical genetic approach.
• To elucidate the impact of CDK12 inhibition on RNAPII dynamics and identify its target genes and pathways.

Main Methods:

• Utilized a chemical genetic strategy with an analog-sensitive CDK12 inhibitor.
• Performed RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to analyze gene expression and RNAPII occupancy.
• Assessed RNAPII processivity and phosphorylation status (RNAPII-Ser2).

Main Results:

• CDK12 kinase activity is essential for the transcription of core DNA replication genes, driving G1/S phase progression.
• CDK12 inhibition leads to RNAPII processivity defects, marked by reduced signal at the 3' ends of long, poly(A)-rich genes.
• While global RNAPII-Ser2 phosphorylation is unaffected, specific CDK12-dependent genes show altered P-Ser2 peak localization correlating with transcription loss.

Conclusions:

• CDK12 catalytic activity provides a novel link between transcriptional regulation and cell cycle control.
• CDK12 inactivation may contribute to cancer genome instability through impaired DNA replication and HR DNA repair pathways.