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Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex

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 a...

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Autores principales: Ekumi, Kingsley M., Paculova, Hana, Lenasi, Tina, Pospichalova, Vendula, Bösken, Christian A., Rybarikova, Jana, Bryja, Vitezslav, Geyer, Matthias, Blazek, Dalibor, Barboric, Matjaz
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357706/
https://www.ncbi.nlm.nih.gov/pubmed/25712099
http://dx.doi.org/10.1093/nar/gkv101
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author Ekumi, Kingsley M.
Paculova, Hana
Lenasi, Tina
Pospichalova, Vendula
Bösken, Christian A.
Rybarikova, Jana
Bryja, Vitezslav
Geyer, Matthias
Blazek, Dalibor
Barboric, Matjaz
author_facet Ekumi, Kingsley M.
Paculova, Hana
Lenasi, Tina
Pospichalova, Vendula
Bösken, Christian A.
Rybarikova, Jana
Bryja, Vitezslav
Geyer, Matthias
Blazek, Dalibor
Barboric, Matjaz
author_sort Ekumi, Kingsley M.
collection PubMed
description 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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spelling pubmed-43577062015-03-20 Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex Ekumi, Kingsley M. Paculova, Hana Lenasi, Tina Pospichalova, Vendula Bösken, Christian A. Rybarikova, Jana Bryja, Vitezslav Geyer, Matthias Blazek, Dalibor Barboric, Matjaz Nucleic Acids Res Gene regulation, Chromatin and Epigenetics 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. Oxford University Press 2015-03-11 2015-02-20 /pmc/articles/PMC4357706/ /pubmed/25712099 http://dx.doi.org/10.1093/nar/gkv101 Text en © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Gene regulation, Chromatin and Epigenetics
Ekumi, Kingsley M.
Paculova, Hana
Lenasi, Tina
Pospichalova, Vendula
Bösken, Christian A.
Rybarikova, Jana
Bryja, Vitezslav
Geyer, Matthias
Blazek, Dalibor
Barboric, Matjaz
Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex
title Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex
title_full Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex
title_fullStr Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex
title_full_unstemmed Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex
title_short Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex
title_sort ovarian carcinoma cdk12 mutations misregulate expression of dna repair genes via deficient formation and function of the cdk12/cyck complex
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357706/
https://www.ncbi.nlm.nih.gov/pubmed/25712099
http://dx.doi.org/10.1093/nar/gkv101
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