Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex
Open Access
- 20 February 2015
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 43 (5), 2575-2589
- https://doi.org/10.1093/nar/gkv101
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.Keywords
This publication has 54 references indexed in Scilit:
- 3′ end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cellsGenes & Development, 2014
- Repair of Strand Breaks by Homologous RecombinationCold Spring Harbor Perspectives in Biology, 2013
- DNA Damage Sensing by the ATM and ATR KinasesCold Spring Harbor Perspectives in Biology, 2013
- Interaction of Cyclin-Dependent Kinase 12/CrkRS with Cyclin K1 Is Required for the Phosphorylation of the C-Terminal Domain of RNA Polymerase IIMolecular and Cellular Biology, 2012
- The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genesGenes & Development, 2011
- Genetic and Structural Variation in the Gastric Cancer Kinome Revealed through Targeted Deep SequencingCancer Research, 2011
- Genome profiling of ERBB2-amplified breast cancersBMC Cancer, 2010
- A Gene-Specific Requirement of RNA Polymerase II CTD Phosphorylation for Sexual Differentiation in S. pombeCurrent Biology, 2010
- Identification of the FANCI Protein, a Monoubiquitinated FANCD2 Paralog Required for DNA RepairCell, 2007
- Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repairProceedings of the National Academy of Sciences of the United States of America, 2005