J 2019

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

CHIRACKAL MANAVALAN, Anil Paul, Květa PILAŘOVÁ, Michael KLUGE, Koen BARTHOLOMEEUSEN, Michal RÁJECKÝ et. al.

Basic information

Original name

CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes

Authors

CHIRACKAL MANAVALAN, Anil Paul (356 India, belonging to the institution), Květa PILAŘOVÁ (203 Czech Republic, belonging to the institution), Michael KLUGE (276 Germany), Koen BARTHOLOMEEUSEN (56 Belgium, belonging to the institution), Michal RÁJECKÝ (203 Czech Republic, 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), Caroline C FRIEDEL (276 Germany) and Dalibor BLAŽEK (203 Czech Republic, guarantor, belonging to the institution)

Edition

EMBO reports, Hoboken, Wiley-Blackwell, 2019, 1469-221X

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10400 1.4 Chemical sciences

Country of publisher

Germany

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

Impact factor

Impact factor: 7.497

RIV identification code

RIV/00216224:14740/19:00107754

Organization unit

Central European Institute of Technology

DOI

UT WoS

000478503100001

Keywords in English

CDK12; G1; S; CTD Ser2 phosphorylation; premature termination and polyadenylation; tandem duplications

Tags

Tags

International impact, Reviewed
Změněno: 24/10/2024 17:01, Ing. Marie Švancarová

Abstract

V originále

CDK12 is a kinase associated with elongating RNA polymerase II (RNAPII) and is frequently mutated in cancer. CDK12 depletion reduces the expression of homologous recombination (HR) DNA repair genes, but comprehensive insight into its target genes and cellular processes is lacking. We use a chemical genetic approach to inhibit analog-sensitive CDK12, and find that CDK12 kinase activity is required for transcription of core DNA replication genes and thus for G1/S progression. RNA-seq and ChIP-seq reveal that CDK12 inhibition triggers an RNAPII processivity defect characterized by a loss of mapped reads from 3 ' ends of predominantly long, poly(A)-signal-rich genes. CDK12 inhibition does not globally reduce levels of RNAPII-Ser2 phosphorylation. However, individual CDK12-dependent genes show a shift of P-Ser2 peaks into the gene body approximately to the positions where RNAPII occupancy and transcription were lost. Thus, CDK12 catalytic activity represents a novel link between regulation of transcription and cell cycle progression. We propose that DNA replication and HR DNA repair defects as a consequence of CDK12 inactivation underlie the genome instability phenotype observed in many cancers.

Links

ED1.1.00/02.0068, research and development project
Name: CEITEC - central european institute of technology
EF17_050/0008496, research and development project
Name: MSCAfellow@MUNI
GA17-13692S, research and development project
Name: Charakterizace nové funkce pro cyklin dependentní kinázu 12 (Cdk12)
Investor: Czech Science Foundation
GA17-17720S, research and development project
Name: Vnitřní vlastnosti RAD51 vlákna a jeho biologické regulace
Investor: Czech Science Foundation
LM2015063, research and development project
Name: Národní infrastruktura chemické biologie (Acronym: CZ-­OPENSCREEN)
Investor: Ministry of Education, Youth and Sports of the CR
MUNI/A/1087/2018, interní kód MU
Name: Molekulární a buněčná biologie pro biomedicínské vědy
Investor: Masaryk University, Category A
MUNI/E/0514/2019, interní kód MU
Name: CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes
Investor: Masaryk University, Promoting quality excellence
90091, large research infrastructures
Name: NCMG