DOI: 10.1101/483958Nov 30, 2018Paper

CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation

BioRxiv : the Preprint Server for Biology
Malgorzata KrajewskaRani E. George

Abstract

The cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and appears to selectively affect the expression of DNA damage response (DDR) and mRNA processing genes. Yet, the mechanism(s) by which it achieves this selectivity remains unclear. Using a highly selective CDK12/13 inhibitor, THZ531, and nascent RNA sequencing, we show that CDK12 inhibition results in gene length-dependent elongation defects, leading to premature cleavage and polyadenylation (PCPA) as well as loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlated with an increased proportion of intronic polyadenylation sites, a feature that was especially prominent among DDR genes. Finally, phosphoproteomic analysis indicated that pre-mRNA processing factors, including those involved in PCPA, are direct phosphotargets of CDKs 12 and 13. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition due primarily to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites.

Related Concepts

Genes
Phosphorylation
DNA-Directed RNA Polymerase
RNA, Messenger
MRNA Cleavage and Polyadenylation Factors
Site
Cyclin-Dependent Kinases
Inhibitors
Tumor Cells, Malignant
Modulated

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