CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F18%3A00106752" target="_blank" >RIV/00216224:14740/18:00106752 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes

Popis výsledku v původním jazyce

Cyclin dependent kinase 12 (CDK12) is involved in RNA Polymerase II (RNAPII) mediated transcription and its kinase domain is frequently mutated in ovarian, breast and prostate cancers. CDK12 depletion leads to a reduction of phosphorylation of serine 2 (P Ser2) in the C terminal domain (CTD) of RNAPII. We have previously reported that CDK12 regulates the transcription of homologous recombination (HR) DNA repair genes. However, comprehensive insight into its target genes and cellular processes remains largely obscure mainly because of the lack of tools to specifically inhibit CDK12. Therefore we generated cells carrying analog sensitive alleles of CDK12 and studied CDK12 catalytic activity in dynamic processes of transcription and cell cycle progression. We show that CDK12 is mostly expressed in G1 phase and its kinase activity is required for optimal G1/S progression. Moreover, the expression of many DNA replication and repair genes are affected upon CDK12 inhibition. To investigate further, we carried out nuclear RNA seq coupled with ChIP seq for RNAPII, P Ser2 RNAPII and P Ser5 RNAPII and revealed that CDK12 inhibition triggered an RNAPII processivity defect, predominantly at relatively long, poly(A) signal rich genes. Thus, CDK12 kinase activity represents a novel link between regulation of transcription and cell cycle progression. We propose that DNA replication and HR DNA repair defects underlie the CDK12 specific genome instability phenotype observed in many cancers.

Název v anglickém jazyce

CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes

Popis výsledku anglicky

Cyclin dependent kinase 12 (CDK12) is involved in RNA Polymerase II (RNAPII) mediated transcription and its kinase domain is frequently mutated in ovarian, breast and prostate cancers. CDK12 depletion leads to a reduction of phosphorylation of serine 2 (P Ser2) in the C terminal domain (CTD) of RNAPII. We have previously reported that CDK12 regulates the transcription of homologous recombination (HR) DNA repair genes. However, comprehensive insight into its target genes and cellular processes remains largely obscure mainly because of the lack of tools to specifically inhibit CDK12. Therefore we generated cells carrying analog sensitive alleles of CDK12 and studied CDK12 catalytic activity in dynamic processes of transcription and cell cycle progression. We show that CDK12 is mostly expressed in G1 phase and its kinase activity is required for optimal G1/S progression. Moreover, the expression of many DNA replication and repair genes are affected upon CDK12 inhibition. To investigate further, we carried out nuclear RNA seq coupled with ChIP seq for RNAPII, P Ser2 RNAPII and P Ser5 RNAPII and revealed that CDK12 inhibition triggered an RNAPII processivity defect, predominantly at relatively long, poly(A) signal rich genes. Thus, CDK12 kinase activity represents a novel link between regulation of transcription and cell cycle progression. We propose that DNA replication and HR DNA repair defects underlie the CDK12 specific genome instability phenotype observed in many cancers.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LQ1601" target="_blank" >LQ1601: CEITEC 2020</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů