CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation
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s41467-019-09703-y.pdf
Description
Published version
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2.1 MB
Format
Unknown
Checksum (MD5)
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Author(s)
Krajewska, Malgorzata
Dries, Ruben
Grassetti, Andrew V.
Dust, Sofia
Gao, Yang
Huang, Hao
Sharma, Bandana
Day, Daniel S.
Kwiatkowski, Nicholas
Pomaville, Monica
Date Issued
April 2019
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Version
Final published version
Abstract
© 2019, The Author(s). 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.
MIT Department
Whitehead Institute for Biomedical Research
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
https://doi.org/10.1038/s41467-019-09703-y
