CDK12 regulates DNA repair genes by suppressing intronic polyadenylation
Open accessAbstract
Mutations that attenuate homologous recombination (HR)-mediated repair promote tumorigenesis and sensitize cells to chemotherapeutics that cause replication fork collapse, a phenotype known as 'BRCAness'1. BRCAness tumours arise from loss-of-function mutations in 22 genes 1. Of these genes, all but one (CDK12) function directly in the HR repair pathway 1. CDK12 phosphorylates serine 2 of the RNA polymerase II C-terminal domain heptapeptide repeat 2-7, a modification that regulates transcription elongation, splicing, and cleavage and polyadenylation 8,9. Genome-wide expression studies suggest that depletion of CDK12 abrogates the expression of several HR genes relatively specifically, thereby blunting HR repair 3-7,10,11. This observation suggests that the mutational status of CDK12 may predict sensitivity to targeted treatments against BRCAness, such as PARP1 inhibitors, and that CDK12 inhibitors may induce sensitization of HR-competent tumours to these treatments 6,7,10,11. Despite growing clinical interest, the mechanism by which CDK12 regulates HR genes remains unknown. Here we show that CDK12 globally suppresses intronic polyadenylation events in mouse embryonic stem cells, enabling the production of full-length gene products. Many HR genes harbour more intronic polyadenylation sites than other expressed genes, and these sites are particularly sensitive to loss of CDK12. The cumulative effect of these sites accounts for the enhanced sensitivity of HR gene expression to CDK12 loss, and we find that this mechanism is conserved in human tumours that contain loss-of-function CDK12 mutations. This work clarifies the function of CDK12 and underscores its potential both as a chemotherapeutic target and as a tumour biomarker.
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CDK12 inactivation causes reduced POLII elongation and premature polyadenylation of select genes enriched in the DNA damage response pathway, resulting in a BRCAness phenotype.
“CDK12 inactivation is known to cause reduced POLII elongation and premature polyadenylation of select genes enriched in the DNA damage response pathway, resulting in a BRCAness phenotype (Blazek et al., 2011; Dubbury et al., 2018; Johnson et al., 2016).”
From Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation (2020) · cites this paper as Dubbury et al., 2018
WRN has been proposed to be a CDK12 target.
“WRN has been proposed to be a CDK12 target (Chan et al., 2019;Dubbury et al., 2018).”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Dubbury et al., 2018
WRN has been identified as a synthetically lethal target of MSI-H cancers.
“recent reports have identified WRN as a synthetically lethal target of MSI-H cancers”
From Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer (2021) · cites this paper as Dubbury et al., 2018
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- Authors
- Dubbury, S. J., Boutz, P. L., & Sharp, P. A.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- University of Rochester Medicine (US)
- Corresponding author
- Sharp, Phillip A.
- Venue
- Nature
- Published
- 2018-11-28
- Volume
- 564
- Issue
- 7734
- Pages
- 141-145
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6328294
- OpenAlex
- W2806593114
- Cited by
- 318
- References
- 51
- Citations by year
- 2026: 48 · 2025: 35 · 2024: 54 · 2023: 36 · 2022: 46 · 2021: 36 · 2020: 39 · 2019: 23
- FWCI
- 8.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (P30-CA14051)
- National Institutes of Health (GM034277, R01-GM034277)
- U.S. Public Health Service (P30-CA14051, R01-GM034277, R01CA133404)
- National Cancer Institute (R01CA133404, P01CA042063, CA14051, R01CA226898, P30CA014051, P30-CA-14051)
- National Institute of General Medical Sciences (R01GM034277, T32GM007287)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- CDK12, intronic polyadenylation, homologous recombination, DNA repair genes, BRCAness, PARP-1 inhibitors, CDK12 inhibitors, tumour biomarkers, chemosensitization, mouse embryonic stem cells
- MeSH terms
- Mouse Embryonic Stem Cells, Poly(ADP-ribose) Polymerase Inhibitors, Poly (ADP-Ribose) Polymerase-1, Loss of Function Mutation, Animals, DNA Damage, DNA Repair, Humans, Introns, Mice, Inbred C57BL, Mutation, Neoplasms, Phosphorylation, RNA Polymerase II, Serine, Biomarkers, Tumor, Cyclin-Dependent Kinases, Polyadenylation, Mice, Molecular Targeted Therapy, Homologous Recombination, Transcription Elongation, Genetic
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