ArticleNucleic acids research2015
Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex.
Article in Nucleic acids research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers, 1 of them a synthesis that pooled it.
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Who cites it
82 citing papers in PubMed, 1 synthesis or guideline pooled it, 151 citations in OpenAlex.
- Prognostic molecular biomarkers in chordomas: A systematic review and identification of clinically usable biomarker panels.Frontiers in oncology · 2022Pooled it
- Secondary Somatic Mutations RestoringCancer discovery · 2017Trial
- Super-enhancer landscape regulated by CDK12 drives retinoblastoma progression.British journal of cancer · 2026Article
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- Regulation of RNA transcript elongation in metazoans and its relevance to disease.Nature reviews. Molecular cell biology · 2026Review
- Novel examples of NMD escape through alternative intronic polyadenylation.NAR genomics and bioinformatics · 2026Article
- CDK12/CDK13 inhibition disrupts transcriptional elongation and replication fork progression in glioblastoma.EMBO molecular medicine · 2026Article
- Absence of synergistic effects by CDK12/13 inhibition in combination with cisplatin or olaparib in ovarian cancer cells.Scientific reports · 2026Article
- Assessment of Homologous Recombination System Gene Expression in Chemologically Induced Carcinogenesis In Vivo Models.Current issues in molecular biology · 2026Article
- New insights into the dule roles CDK12 in human cancers: Mechanisms and interventions for cancer therapy.Journal of pharmaceutical analysis · 2025Review
- Defining CDK12 as a tumor suppressor and therapeutic target in mouse models of tubo-ovarian high-grade serous carcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Mechanistic Roles of Transcriptional Cyclin-Dependent Kinases in Oncogenesis: Implications for Cancer Therapy.Cancers · 2025Review
- Absence of CDK12 in oocyte leads to female infertility.Cell death & disease · 2025Article
- Article
- Development of CDK12 as a Cancer Therapeutic Target and Related Inhibitors.Current cancer drug targets · 2025Review
- Synthetic Lethal Targeting of CDK12-Deficient Prostate Cancer with PARP Inhibitors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- CDK12 loss drives prostate cancer progression, transcription-replication conflicts, and synthetic lethality with paralog CDK13.Cell reports. Medicine · 2024Article
- Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition.Cell reports. Medicine · 2024Article
- Prostate Cancer: A Review of Genetics, Current Biomarkers and Personalised Treatments.Cancer reports (Hoboken, N.J.) · 2024Review
- Loss of heterozygosity impacts MHC expression on the immune microenvironment in CDK12-mutated prostate cancer.Molecular cytogenetics · 2024Article
22 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Cdk12/CycK complex promotes expression of a subset of RNA polymerase II genes, including those of the DNA damage response. CDK12 is among only nine genes with recurrent somatic mutations in high-grade serous ovarian carcinoma. However, the influence of these mutations on the Cdk12/CycK complex and their link to cancerogenesis remain ill-defined. Here, we show that most mutations prevent formation of the Cdk12/CycK complex, rendering the kinase inactive. By examining the mutations within the Cdk12/CycK structure, we find that they likely provoke structural rearrangements detrimental to Cdk12 activation. Our mRNA expression analysis of the patient samples containing the CDK12 mutations reveals coordinated downregulation of genes critical to the homologous recombination DNA repair pathway. Moreover, we establish that the Cdk12/CycK complex occupies these genes and promotes phosphorylation of RNA polymerase II at Ser2. Accordingly, we demonstrate that the mutant Cdk12 proteins fail to stimulate the faithful DNA double strand break repair via homologous recombination. Together, we provide the molecular basis of how mutated CDK12 ceases to function in ovarian carcinoma. We propose that CDK12 is a tumor suppressor of which the loss-of-function mutations may elicit defects in multiple DNA repair pathways, leading to genomic instability underlying the genesis of the cancer.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.