AbstractsBiology & Animal Science

Cyclin-dependent kinases (Cdks) are an evolutionary conserved group of serine/threonine protein kinases involved in critical cellular processes such as cell cycle and transcription. Cdk7 and CCRK (cell cycle related kinase; also known as Cdk20) form a separate branch together in a phylogenetic alignment of Cdks family. This study here has identified distinct cellular functions of these two kinases and does not support overlapping functions as suggested by orthologs in yeast. Cdk7 together with cyclin H and Mat1 forming the kinase subcomplex of TFIIH basal transcription factor complex is proposed to regulate RNA polymerase II (Pol II) mediated mRNA synthesis by phosphorylating the serine-5 (Ser5) residues of POL II large subunit C-terminal domain (CTD). Investigations in the genetic systems generated here allowing acute depletion of the Cdk7 subcomplex demonstrate that Cdk7 is the mammalian Ser5 phosphorylating kinase and is required for general transcription noted by analysis of newly transcribed RNAs. The analysis also reveals a requirement of Cdk7 for RNA polymerase I mediated rRNA synthesis. The reduced transcription following Cdk7 disruption is associated with changes on chromatin but not reflected in steady-state RNA levels due to increased RNA stability. These results also reveal a coupled regulation of transcription and RNA degradation. A tissue-specific function of the Cdk7 subcomplex is identified as a physiological roadblock to adipogenesis by phosphorylating the master transcription factor of adipogenic program-peroxisome proliferator-activated receptor gamma (PPARγ). The observation that the Cdk7 subcomplex is absent from adipose tissues indicates the so-called basal transcription machinery has very diverse composition in differentiated cells. CCRK is involved in regulating formation of primary cilium, a sensory organelle acting as a signaling hub in the cell. CCRK promotes cell cycle progression by inhibiting ciliogenesis. In glioblastoma cells, reducing the deregulated high level of CCRK or two related substrate kinases of CCRK restores cilia, leading to decreased glioblastoma cell proliferation. Here is identified the first kinase cascade used by tumor cells to disrupt cilia for a growth advantage and offered new therapeutic possibilities. Not avaiable