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

Malgorzata Krajewska, Ruben Dries, Andrew V. Grassetti, Sofia Dust, Yang Gao, Hao Huang, Bandana Sharma, Daniel S. Day, Nicholas Kwiatkowski, Monica Pomaville, Oliver Dodd, Edmond Chipumuro, Tinghu Zhang, Arno L. Greenleaf, Guo-Cheng Yuan, Nathanael S. Gray, Richard A. Young, Matthias Geyer, Scott A. Gerber and Rani E. George ()
Additional contact information
Malgorzata Krajewska: Dana-Farber Cancer Institute and Boston Children’s Hospital
Ruben Dries: Dana-Farber Cancer Institute and Boston Children’s Hospital
Andrew V. Grassetti: Geisel School of Medicine at Dartmouth
Sofia Dust: University of Bonn
Yang Gao: Dana-Farber Cancer Institute and Boston Children’s Hospital
Hao Huang: Dana-Farber Cancer Institute and Boston Children’s Hospital
Bandana Sharma: Dana-Farber Cancer Institute and Boston Children’s Hospital
Daniel S. Day: Massachusetts Institute of Technology
Nicholas Kwiatkowski: Dana-Farber Cancer Institute
Monica Pomaville: Dana-Farber Cancer Institute and Boston Children’s Hospital
Oliver Dodd: Dana-Farber Cancer Institute and Boston Children’s Hospital
Edmond Chipumuro: Dana-Farber Cancer Institute and Boston Children’s Hospital
Tinghu Zhang: Dana-Farber Cancer Institute
Arno L. Greenleaf: Duke University Medical Center
Guo-Cheng Yuan: Dana-Farber Cancer Institute
Nathanael S. Gray: Dana-Farber Cancer Institute
Richard A. Young: Massachusetts Institute of Technology
Matthias Geyer: University of Bonn
Scott A. Gerber: Geisel School of Medicine at Dartmouth
Rani E. George: Dana-Farber Cancer Institute and Boston Children’s Hospital

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract Cyclin-dependent kinase 12 (CDK12) modulates transcription elongation by phosphorylating the carboxy-terminal domain of RNA polymerase II and selectively affects the expression of genes involved in the DNA damage response (DDR) and mRNA processing. Yet, the mechanisms underlying such selectivity remain unclear. Here we show that CDK12 inhibition in cancer cells lacking CDK12 mutations results in gene length-dependent elongation defects, inducing premature cleavage and polyadenylation (PCPA) and loss of expression of long (>45 kb) genes, a substantial proportion of which participate in the DDR. This early termination phenotype correlates with an increased number of intronic polyadenylation sites, a feature especially prominent among DDR genes. Phosphoproteomic analysis indicated that CDK12 directly phosphorylates pre-mRNA processing factors, including those regulating PCPA. These results support a model in which DDR genes are uniquely susceptible to CDK12 inhibition primarily due to their relatively longer lengths and lower ratios of U1 snRNP binding to intronic polyadenylation sites.

Date: 2019
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DOI: 10.1038/s41467-019-09703-y

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