Cited by 336RNA Research and SplicingDNA Repair MechanismsPARP inhibition in cancer therapy

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CDK12 regulates DNA repair genes by suppressing intronic polyadenylation

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Dubbury, Sara J., Boutz, Paul L., Sharp, Phillip A.·2018·Nature

DOI 10.1038/s41586-018-0758-yPMC PMC6328294

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Abstract

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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Additional file 4 of Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer
Lautert-Dutra, W., M. Melo, C., Chaves, L. P., Crozier, C., P. Saggioro, F., B. dos Reis, R., Bayani, J., Bonatto, S. L., & Squire, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.26716228
Additional file 5 of Splicing targeting drugs highlight intron retention as an actionable vulnerability in advanced prostate cancer
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Additional file 3 of Splicing targeting drugs highlight intron retention as an actionable vulnerability in advanced prostate cancer
Naro, C., Antonioni, A., Medici, V., Caggiano, C., Jolly, A., de la Grange, P., Bielli, P., Paronetto, M. P., & Sette, C. (2024) · Figshare · doi:10.6084/m9.figshare.26685846
Additional file 8 of Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer
Lautert-Dutra, W., M. Melo, C., Chaves, L. P., Crozier, C., P. Saggioro, F., B. dos Reis, R., Bayani, J., Bonatto, S. L., & Squire, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.26716240
Additional file 3 of Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids
Cesari, E., Ciucci, A., Pieraccioli, M., Caggiano, C., Nero, C., Bonvissuto, D., Sillano, F., Buttarelli, M., Piermattei, A., Loverro, M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26590215
Additional file 6 of Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer
Lautert-Dutra, W., M. Melo, C., Chaves, L. P., Crozier, C., P. Saggioro, F., B. dos Reis, R., Bayani, J., Bonatto, S. L., & Squire, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.26716234
Additional file 5 of Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer
Lautert-Dutra, W., M. Melo, C., Chaves, L. P., Crozier, C., P. Saggioro, F., B. dos Reis, R., Bayani, J., Bonatto, S. L., & Squire, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.26716231
Additional file 2 of Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids
Cesari, E., Ciucci, A., Pieraccioli, M., Caggiano, C., Nero, C., Bonvissuto, D., Sillano, F., Buttarelli, M., Piermattei, A., Loverro, M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26590212
Additional file 1 of Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids
Cesari, E., Ciucci, A., Pieraccioli, M., Caggiano, C., Nero, C., Bonvissuto, D., Sillano, F., Buttarelli, M., Piermattei, A., Loverro, M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26590209
Additional file 4 of Splicing targeting drugs highlight intron retention as an actionable vulnerability in advanced prostate cancer
Naro, C., Antonioni, A., Medici, V., Caggiano, C., Jolly, A., de la Grange, P., Bielli, P., Paronetto, M. P., & Sette, C. (2024) · Figshare · doi:10.6084/m9.figshare.26685849
Additional file 1 of Splicing targeting drugs highlight intron retention as an actionable vulnerability in advanced prostate cancer
Naro, C., Antonioni, A., Medici, V., Caggiano, C., Jolly, A., de la Grange, P., Bielli, P., Paronetto, M. P., & Sette, C. (2024) · Figshare · doi:10.6084/m9.figshare.25302963
Additional file 3 of Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer
Lautert-Dutra, W., M. Melo, C., Chaves, L. P., Crozier, C., P. Saggioro, F., B. dos Reis, R., Bayani, J., Bonatto, S. L., & Squire, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.26716225
Additional file 4 of Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids
Cesari, E., Ciucci, A., Pieraccioli, M., Caggiano, C., Nero, C., Bonvissuto, D., Sillano, F., Buttarelli, M., Piermattei, A., Loverro, M., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26590218
Additional file 1 of Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer
Lautert-Dutra, W., M. Melo, C., Chaves, L. P., Crozier, C., P. Saggioro, F., B. dos Reis, R., Bayani, J., Bonatto, S. L., & Squire, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.26716219
Additional file 9 of Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer
Lautert-Dutra, W., M. Melo, C., Chaves, L. P., Crozier, C., P. Saggioro, F., B. dos Reis, R., Bayani, J., Bonatto, S. L., & Squire, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.26716243
Additional file 7 of Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer
Lautert-Dutra, W., M. Melo, C., Chaves, L. P., Crozier, C., P. Saggioro, F., B. dos Reis, R., Bayani, J., Bonatto, S. L., & Squire, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.26716237
Additional file 2 of Splicing targeting drugs highlight intron retention as an actionable vulnerability in advanced prostate cancer
Naro, C., Antonioni, A., Medici, V., Caggiano, C., Jolly, A., de la Grange, P., Bielli, P., Paronetto, M. P., & Sette, C. (2024) · Figshare · doi:10.6084/m9.figshare.25303133
Additional file 2 of Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer
Lautert-Dutra, W., M. Melo, C., Chaves, L. P., Crozier, C., P. Saggioro, F., B. dos Reis, R., Bayani, J., Bonatto, S. L., & Squire, J. A. (2024) · Figshare · doi:10.6084/m9.figshare.26716222

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.
ORCID: Dubbury, Sara J.
Boutz, Paul L.
Sharp, Phillip A.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2018-11-28
Volume: 564
Issue: 7734
Pages: 141-145
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-018-0758-y
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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