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

Abstract

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.

CDK12: A Potent Target and Biomarker for Human Cancer Therapy

“…Interestingly, RNAP II transcription is not globally impaired in cells without CDK12/cyclin K complex [13]. Chirackal Manavalan et al have found that the inhibition of CDK12 does not affect Ser2 phosphorylation level as well as global transcription but diminishes RNAP II processivity accompanied by transcript shortening of DNA replication genes, which is consistent with defective transcription elongation [9]. Moreover, CDK12 also plays a role in co-transcriptional processing of genes such as MYC, particularly at its 3 end [41].…”

“…In 2010, CDK12 was first demonstrated as a transcription-associated CTD kinase in Drosophila [24]. At present, CDK12 is regarded as a transcription-associated CDK, which phosphorylates the CTD of RNAP II [8,9,24,37]. RNAP II is responsible for RNA synthesis of eukaryotic genes.…”

“…In addition, CDK12 and cyclin K are considered to be proteins associated with RNAP II and transcription elongation [24,43]. CDK12 binds cyclin K to form a CDK12/cyclin K complex, which regulates phosphorylation of Ser2 in the CTD of RNAP II and expression of DDR genes, DNA replication genes and DNA repair genes [9,13].…”

PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

“…Cyclin-dependent kinase 12 (CDK12) modulates transcription by acting on RNA polymerase II. In vitro, CDK12 loss-of-function mutations and CDK12 inhibition (CDK12i) reduced the expression of HR-related genes, including BRCA1, ATR, and Fanconi-anemia pathway genes, due to premature cleavage and polyadenylation [151][152][153], leading to reduced capacity for HR repair [154][155][156]. This mechanism of re-inducing HR underlies the synthetic lethality between CDK12i and PARPi, seen in models of HGSOC [157] and breast cancer [156] and may be effective for PARPi-resistant disease in which HR is restored.…”

CVB3 VP1 interacts with MAT1 to inhibit cell proliferation by interfering with Cdk-activating kinase complex activity in CVB3-induced acute pancreatitis

“…Phosphorylation of pRb at several clusters of sites could inhibit E2F binding, especially at the C-terminal sites such as Ser780, Ser795 and Ser807/811 [26]. The activated RNA polymerase II is then able to bind DNA and start transcription of S-phase genes [27][28][29][30]. The CDK-Rb-E2F pathway is undoubtedly responsible for G1 phase progression and transition to the S phase [25].…”