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

AP. Chirackal Manavalan, K. Pilarova, M. Kluge, K. Bartholomeeusen, M. Rajecky, J. Oppelt, P. Khirsariya, K. Paruch, L. Krejci, CC. Friedel, D. Blazek,

. 2019 ; 20 (9) : e47592. [pub] 20190725

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc20023691

Grantová podpora
206292/E/17/Z Wellcome Trust Collaborative Grant - International
CZ.02.2.69/0.0/0.0/17_050/0008496 MSCAfellow@MUNI - International
CESNET LM2015042 Projects of Large Research, Development, and Innovations Infrastructures - International
LM2015063 National Infrastructure for Chemical Biology - International
MUNI/E/0514/2019 The Grant Agency of Masaryk University - International
CZ.1.05/1.1.00/02.0068 CEITEC - International
FR2938/7-1 Deutsche Forschungsgemeinschaft - International
CRC 1123 (Z2) Deutsche Forschungsgemeinschaft - International
17-13692S Czech Science Foundation - International
17-17720S Czech Science Foundation - International
LQ1605 MEYS CR - International

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.

Citace poskytuje Crossref.org

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$a Chirackal Manavalan, Anil Paul $u Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic.
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$a 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.
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$a Khirsariya, Prashant $u Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic. Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
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$a Paruch, Kamil $u Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Brno, Czech Republic. Center of Biomolecular and Cellular Engineering, International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic.
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