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

CHIRACKAL MANAVALAN, Anil Paul, Květa PILAŘOVÁ, M. KLUGE, Koen BARTHOLOMEEUSEN, Jan OPPELT, PrashantKumar KHIRSARIYA, Kamil PARUCH, Lumír KREJČÍ, C. FRIEDEL and Dalibor BLAŽEK. CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes. In 2018 ASCB | EMBO Annual Meeting. 2018.

Basic information

• Original name: CDK12 kinase activity controls G1/S progression by regulating optimal transcription of core DNA replication genes
• Authors: CHIRACKAL MANAVALAN, Anil Paul (356 India, belonging to the institution), Květa PILAŘOVÁ (203 Czech Republic, belonging to the institution), M. KLUGE (276 Germany), Koen BARTHOLOMEEUSEN (56 Belgium, belonging to the institution), Jan OPPELT (203 Czech Republic, belonging to the institution), PrashantKumar KHIRSARIYA (356 India, belonging to the institution), Kamil PARUCH (203 Czech Republic, belonging to the institution), Lumír KREJČÍ (203 Czech Republic, belonging to the institution), C. FRIEDEL (276 Germany) and Dalibor BLAŽEK (203 Czech Republic, guarantor, belonging to the institution).
• Edition: 2018 ASCB | EMBO Annual Meeting, 2018.

Other information

• Original language: English
• Type of outcome: Conference abstract
• Field of Study: 10608 Biochemistry and molecular biology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• RIV identification code: RIV/00216224:14740/18:00106752
• Organization unit: Central European Institute of Technology
• Keywords in English: CDK12kinase; DNA replication genes
• Tags: rivok
• Tags: International impact, Reviewed

Abstract

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.

Links

• LQ1601, research and development project: Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR