CK2 (formerly termed "casein kinase 2") is a ubiquitous, highly pleiotropic and constitutively active Ser/Thr protein kinase whose implication in neoplasia, cell survival, and virus infection is supported by an increasing number of arguments. Here an updated inventory of 307 CK2 protein substrates is presented. More than one-third of these are implicated in gene expression and protein synthesis as being either transcriptional factors (60) or effectors of DNA/RNA structure (50) or translational elements. Also numerous are signaling proteins and proteins of viral origin or essential to virus life cycle. In comparison, only a minority of CK2 targets (a dozen or so) are classical metabolic enzymes. An analysis of 308 sites phosphorylated by CK2 highlights the paramount relevance of negatively charged side chains that are (by far) predominant over any other residues at positions n+3 (the most crucial one), n+1, and n+2. Based on this signature, it is predictable that proteins phosphorylated by CK2 are much more numerous than those identified to date, and it is possible that CK2 alone contributes to the generation of the eukaryotic phosphoproteome more so than any other individual protein kinase. The possibility that CK2 phosphosites play some global role, e.g., by destabilizing alpha helices, counteracting caspase cleavage, and generating adhesive motifs, will be discussed.

One-thousand-and-one substrates of protein kinase CK2?

https://rnajc.ucsf.edu/sites/rnajc.ucsf.edu/files/cmyc.pdf

c-Myc regulates transcriptional pause release.

Gene expression in eukaryotes requires several multi-component cellular machines. Each machine carries out a separate step in the gene expression pathway, which includes transcription, several pre-messenger RNA processing steps and the export of mature mRNA to the cytoplasm. Recent studies lead to the view that, in contrast to a simple linear assembly line, a complex and extensively coupled network has evolved to coordinate the activities of the gene expression machines. The extensive coupling is consistent with a model in which the machines are tethered to each other to form 'gene expression factories' that maximize the efficiency and specificity of each step in gene expression.

http://m.docente.unife.it/franco.pagani/lezioni-1010/Maniatis%20Reed%20review%20NAture2002%20copy.pdf

An extensive network of coupling among gene expression machines

Targeted Recruitment of Set1 Histone Methylase by Elongating Pol II Provides a Localized Mark and Memory of Recent Transcriptional Activity

Controlling the Elongation Phase of Transcription with P-TEFb

NELF, a Multisubunit Complex Containing RD, Cooperates with DSIF to Repress RNA Polymerase II Elongation

We report the identification of a transcription elongation factor from HeLa cell nuclear extracts that causes pausing of RNA polymerase II (Pol II) in conjunction with the transcription inhibitor 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB). This factor, termed DRB sensitivity-inducing factor (DSIF), is also required for transcription inhibition by H8. DSIF has been purified and is composed of 160-kD (p160) and 14-kD (p14) subunits. Isolation of a cDNA encoding DSIF p160 shows it to be a homolog of the Saccharomyces cerevisiae transcription factor Spt5. Recombinant Supt4h protein, the human homolog of yeast Spt4, is functionally equivalent to DSIF p14, indicating that DSIF is composed of the human homologs of Spt4 and Spt5. In addition to its negative role in elongation, DSIF is able to stimulate the rate of elongation by RNA Pol II in a reaction containing limiting concentrations of ribonucleoside triphosphates. A role for DSIF in transcription elongation is further supported by the fact that p160 has a region homologous to the bacterial elongation factor NusG. The combination of biochemical studies on DSIF and genetic analysis of Spt4 and Spt5 in yeast, also in this issue, indicates that DSIF associates with RNA Pol II and regulates its processivity in vitro and in vivo.

/pdf/dsif-a-novel-transcription-elongation-factor-that-regulates-1pvp8iomns.pdf

Dsif, a novel transcription elongation factor that regulates rna polymerase ii processivity, is composed of human spt4 and spt5 homologs

Recently, a positive and a negative elongation factor, implicated in 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) inhibition of transcription elongation, has been identified. P-TEFb is a positive transcription elongation factor and the DRB-sensitive kinase that phosphorylates the C-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II). PITALRE, a member of the Cdc2 family of protein kinases, is the catalytic subunit of P-TEFb. DSIF is a human homolog of the yeast Spt4-Spt5 complex and renders elongation of transcription sensitive to DRB. DRB sensitivity-inducing factor (DSIF) binds to RNA Pol II and may directly regulate elongation. Here we show a functional interaction between P-TEFb and DSIF. The reduction of P-TEFb activity induced by either DRB, antibody against PITALRE, or immunodepletion resulted in a negative effect of DSIF on transcription. DSIF acts at an early phase of elongation, and the prior action of P-TEFb makes transcription resistant to DSIF. The state of phosphorylation of CTD determines the DSIF-RNA Pol II interaction, and may provide a direct link between P-TEFb and DSIF. Taken together, this study reveals a molecular basis for DRB action and suggests that P-TEFb stimulates elongation by alleviating the negative action of DSIF.

Evidence that p-tefb alleviates the negative effect of dsif on rna polymerase ii-dependent transcription in vitro

Structure and function of the human transcription elongation factor DSIF.

Casein kinase II (CKII) is thought to regulate a broad range of transcription factors, but its mode of action is not well characterized. We previously showed that CKII is co-purified with the ATF family of transcription factors using DNA-affinity latex beads. Here we report a functional and physical interaction between CKII and transcription factors. We demonstrate that CKII binds through its catalytic alpha and alpha' subunits to the basic leucine zipper (bZIP) DNA-binding domains of many transcription factors, including ATF1. Kinetic analysis using a surface plasmon resonance sensor suggests that CKII loosely associates with ATF1 in vivo . Deletion of the bZIP domain of ATF1 markedly reduces its phosphorylation by CKII, suggesting that the bZIP recruits CKII to the vicinity of the target site. ATF1-CKII complex is also formed on DNA. Using CKIIalpha fusedto a heterologous DNA-binding domain, we also demonstrate that CKII, when bound to DNA, efficiently phosphorylates its substrate, which is bound to the same DNA molecule. Taken together, CKII may regulate transcription (and possibly other events) by phosphorylating proteins on DNA.

/pdf/casein-kinase-ii-interacts-with-the-bzip-domains-of-several-2hobcn7jk5.pdf

Toshiyuki Takagi

Papers

NELF, a Multisubunit Complex Containing RD, Cooperates with DSIF to Repress RNA Polymerase II Elongation

Dsif, a novel transcription elongation factor that regulates rna polymerase ii processivity, is composed of human spt4 and spt5 homologs

Evidence that p-tefb alleviates the negative effect of dsif on rna polymerase ii-dependent transcription in vitro

Structure and function of the human transcription elongation factor DSIF.

Casein kinase II interacts with the bZIP domains of several transcription factors