Informace o publikaci

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

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EKUMI Kingsley M. PACULOVÁ Hana LENASI Tina POSPÍCHALOVÁ Vendula BOESKEN Christian A. RYBAŘÍKOVÁ Jana BRYJA Vítězslav GEYER Matthias BLAŽEK Dalibor BARBORIC Matjaz

Rok publikování 2015
Druh Článek v odborném periodiku
Časopis / Zdroj Nucleic Acids Research
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www http://nar.oxfordjournals.org/content/43/5/2575
Doi http://dx.doi.org/10.1093/nar/gkv101
Obor Genetika a molekulární biologie
Klíčová slova RNA-POLYMERASE-II; PRE-MESSENGER-RNA; MAINTAINS GENOMIC STABILITY; CYCLIN K/CDK12 COMPLEX; TRANSCRIPTION IN-VIVO; C-TERMINAL DOMAIN; HOMOLOGOUS RECOMBINATION; P-TEFB; KINASE; ELONGATION
Přiložené soubory
Popis 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 thesemutations 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 cance
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