Informace o publikaci

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

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CHIRACKAL MANAVALAN Anil Paul PILAŘOVÁ Květa KLUGE Michael BARTHOLOMEEUSEN Koen RÁJECKÝ Michal OPPELT Jan KHIRSARIYA PrashantKumar PARUCH Kamil KREJČÍ Lumír FRIEDEL Caroline C BLAŽEK Dalibor

Rok publikování 2019
Druh Článek v odborném periodiku
Časopis / Zdroj EMBO reports
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www https://www.embopress.org/doi/full/10.15252/embr.201847592
Doi http://dx.doi.org/10.15252/embr.201847592
Klíčová slova CDK12; G1; S; CTD Ser2 phosphorylation; premature termination and polyadenylation; tandem duplications
Popis 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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