CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation
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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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CDK12 forms a complex with CCNK to act as a transcriptional regulator of genes critically involved in DDR pathways.
“CDK12 forms a complex with CCNK to act as a transcriptional regulator of genes critically involved in DDR pathways (Blazek et al., 2011;Krajewska et al., 2019).”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Krajewska et al., 2019
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Self-citation
- Authors
- Krajewska, M., Dries, R., Grassetti, A. V., Dust, S., Gao, Y., Huang, H., Sharma, B., Day, D. S., Kwiatkowski, N., Pomaville, M., Dodd, O., Chipumuro, E., Zhang, T., Greenleaf, A. L., Yuan, G.-C., Gray, N. S., Young, R. A., Geyer, M., Gerber, S. A., & George, R. E.
- Affiliations
- Boston Children's Hospital (US)
- Dartmouth College (US)
- University of Bonn (DE)
- Whitehead Institute for Biomedical Research (US)
- Dana-Farber Cancer Institute (US)
- Duke Medical Center (US)
- Harvard University (US)
- Corresponding author
- George, Rani E.
- ORCID
- Venue
- Nature Communications
- Published
- 2019-04-15
- Volume
- 10
- Issue
- 1
- Pages
- 1757-1757
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6465371
- OpenAlex
- W2952112291
- Cited by
- 281
- References
- 83
- Citations by year
- 2026: 41 · 2025: 33 · 2024: 55 · 2023: 32 · 2022: 46 · 2021: 34 · 2020: 26 · 2019: 14
- FWCI
- 9.96
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Alex's Lemonade Stand Foundation for Childhood Cancer
- Rally Foundation
- Dana-Farber Cancer Institute
- National Institutes of Health (1s10od016212-01, CA154303, CA154303-06)
- National Cancer Institute (R01CA179483, P01CA154303, R01CA197336, P30CA014236)
- National Institute of General Medical Sciences (R01GM122846)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- CDK12, DNA damage response genes, transcription elongation, gene length, pre-mRNA processing, U1 snRNP, phosphoproteomics, cancer cells
- MeSH terms
- Chromatography, High Pressure Liquid, Chromatography, Liquid, DNA Damage, DNA Repair, Humans, Models, Molecular, Phosphorylation, RNA Processing, Post-Transcriptional, Cyclin-Dependent Kinases, Polyadenylation, Cell Line, Tumor, Tandem Mass Spectrometry
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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