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

Nat Commun. 2019 Apr 15;10(1):1757. doi: 10.1038/s41467-019-09703-y.

Malgorzata Krajewska ¹ ², Ruben Dries ¹ ² ³, Andrew V Grassetti ⁴, Sofia Dust ⁵, Yang Gao ¹ ², Hao Huang ¹ ², Bandana Sharma ¹, Daniel S Day ⁶, Nicholas Kwiatkowski ⁷, Monica Pomaville ¹, Oliver Dodd ¹, Edmond Chipumuro ¹, Tinghu Zhang ⁷, Arno L Greenleaf ⁸, Guo-Cheng Yuan ³ ⁹, Nathanael S Gray ⁷ ¹⁰, Richard A Young ⁶, Matthias Geyer ⁵, Scott A Gerber ⁴, Rani E George ¹¹ ¹²

Affiliations

1 Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, 02115, USA.
2 Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA.
3 Departments of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
4 Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, 03756, USA.
5 Institute of Structural Biology, University of Bonn, 53127, Bonn, Germany.
6 Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
7 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
8 Department of Biochemistry, Duke University Medical Center, Durham, NC, 27710, USA.
9 Harvard School of Public Health, Boston, MA, 02115, USA.
10 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
11 Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, 02115, USA. [email protected].
12 Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA. [email protected].

PMID: 30988284 DOI: 10.1038/s41467-019-09703-y

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.

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