Threonine-4 of mammalian RNA polymerase II CTD is targeted by Polo-like kinase 3 and required for transcriptional elongation

Hintermair, Corinna; Heidemann, Martin; Koch, Frank‐Thomas; Descostes, Nicolas; Gut, Marta; Fenouil, Romain; Ferrier, Pierre; Flatley, Andrew; Kremmer, Elisabeth; Chapman, Rob D.; Andrau, Jean-Christophe; Eick, Dirk

doi:10.1038/emboj.2012.123

Cited by 127 publications

(219 citation statements)

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“…23 Moreover, RNAPII levels that are maximally phosphorylated on serine 2 tend to peak downstream of the site of polyadenylation. [19][20][21][22] The fact that the peak of 3 0 pausing and Ser2 phosphorylation occurs right at the site of 3 0 end cleavage in worms is an interesting difference from mammals. Therefore, Ser2p at 3 0 ends of internal genes in operons most probably functions in guiding 3 0 end formation, similar to terminal and single gene 3 0 ends.…”

Section: Discussionmentioning

confidence: 99%

“…1A) shows total RNAPII in the promoter region (indicated by H3K9ac), but no signal at that location with the Ser2 phospho-antibody, as expected based on ChIP results in other organisms. [19][20][21][22] The levels of RNAPII fluctuate throughout the body of the soc-2 gene in a pattern roughly matching the presence of exons (Fig. 1A).…”

Section: Rnapii Distribution On C Elegans Single Genesmentioning

confidence: 99%

“…ChIP experiments have shown that RNAPII that is heavily phosphorylated at Ser2 generally occurs as a peak downstream of the poly-A site. [19][20][21][22] Mutant RNAPII in which the serines at position 2 within the CTD have been mutated to alanines showed a defect in 3 0 end cleavage. 23 Furthermore, experiments done using the human B-globin gene have shown that inactivation of the poly A signal sequence (AAUAAA) inhibits Ser2 hyperphosphorylation 1-2 kb downstream of the gene.…”

Section: Introductionmentioning

confidence: 99%

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Localization of RNAPII and 3′ end formation factor CstF subunits onC. elegansgenes and operons

2016

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Transcription termination is mechanistically coupled to pre-mRNA 3 0 end formation to prevent transcription much beyond the gene 3 0 end. C. elegans, however, engages in polycistronic transcription of operons in which 3 0 end formation between genes is not accompanied by termination. We have performed RNA polymerase II (RNAPII) and CstF ChIP-seq experiments to investigate at a genome-wide level how RNAPII can transcribe through multiple poly-A signals without causing termination. Our data shows that transcription proceeds in some ways as if operons were composed of multiple adjacent single genes. Total RNAPII shows a small peak at the promoter of the gene cluster and a much larger peak at 3 0 ends. These 3 0 peaks coincide with maximal phosphorylation of Ser2 within the C-terminal domain (CTD) of RNAPII and maximal localization of the 3 0 end formation factor CstF. This pattern occurs at all 3 0 ends including those at internal sites in operons where termination does not occur. Thus the normal mechanism of 3 0 end formation does not always result in transcription termination. Furthermore, reduction of CstF50 by RNAi did not substantially alter the pattern of CstF64, total RNAPII, or Ser2 phosphorylation at either internal or terminal 3 0 ends. However, CstF50 RNAi did result in a subtle reduction of CstF64 binding upstream of the site of 3 0 cleavage, suggesting that the CstF50/CTD interaction may facilitate bringing the 3 0 end machinery to the transcription complex.

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Section: Discussionmentioning

confidence: 99%

Section: Rnapii Distribution On C Elegans Single Genesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Localization of RNAPII and 3′ end formation factor CstF subunits onC. elegansgenes and operons

2016

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“…The Ser2, Thr4, Ser7, and Tyr1 hydroxyl groups are inessential for vegetative growth of fission yeast (6). In metazoa, Ser2, Thr4, and Ser7 are critical for cell viability and/or specific steps of transcription or RNA processing, e.g., because these coding cues are recognized by components of the processing machinery, some of which are unique to metazoa (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Individual letters of the RNA polymerase II CTD code govern distinct gene expression programs in fission yeast

Schwer

Bitton

Sánchez

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The primary structure and phosphorylation pattern of the tandem Y 1 S 2 P 3 T 4 S 5 P 6 S 7 repeats of the RNA polymerase II carboxyl-terminal domain (CTD) comprise an informational code that coordinates transcription, chromatin modification, and RNA processing. To gauge the contributions of individual CTD coding "letters" to gene expression, we analyzed the poly(A) + transcriptomes of fission yeast mutants that lack each of the four inessential CTD phosphoacceptors: Tyr1, Ser2, Thr4, and Ser7. There was a hierarchy of CTD mutational effects with respect to the number of dysregulated protein-coding RNAs, with S2A (n = 227) >> Y1F (n = 71) > S7A (n = 58) >> T4A (n = 7). The majority of the protein-coding RNAs affected in Y1F cells were coordinately affected by S2A, suggesting that Tyr1-Ser2 constitutes a two-letter code "word." Y1F and S2A elicited increased expression of genes encoding proteins involved in iron uptake (Frp1, Fip1, Fio1, Str3, Str1, Sib1), without affecting the expression of the genes that repress the iron regulon, implying that Tyr1-Ser2 transduces a repressive signal. Y1F and S2A cells had increased levels of ferric reductase activity and were hypersensitive to phleomycin, indicative of elevated intracellular iron. The T4A and S7A mutations had opposing effects on the phosphate response pathway. T4A reduced the expression of two genes encoding proteins involved in phosphate acquisition (the Pho1 acid phosphatase and the phosphate transporter SPBC8E4.01c), without affecting the expression of known genes that regulate the phosphate response pathway, whereas S7A increased pho1 + expression. These results highlight specific cellular gene expression programs that are responsive to distinct CTD cues.iron homeostasis | phosphate homeostasis | transcription profiling T he carboxyl-terminal domain (CTD) of the Rpb1 subunit of RNA polymerase II (Pol II) consists of tandemly repeated heptapeptides of consensus sequence Y 1 S 2 P 3 T 4 S 5 P 6 S 7 . The inherently plastic CTD structure is modulated by phosphorylation of the Tyr1, Ser2, Thr4, Ser5, and Ser7 residues and by cis-trans isomerization of the prolines (1, 2). With as many as 128 n potential CTD primary structures (where n is the number of heptads), the CTD provides information about the state of the transcription machinery-a CTD code-that is "read" by CTD receptor proteins that control transcription, modify chromatin structure, and catalyze or regulate mRNA capping, splicing, and polyadenylation (1, 2).Basic informational rules that govern the CTD code have been elucidated by genetically manipulating the composition and structure of the Rpb1 CTD in the fission yeast Schizosaccharomyces pombe (3-7). By introducing alanines and conservative mutations in lieu of Tyr1, Ser2, Pro3, Thr4, Ser5, Pro6, and Ser7 of every consensus heptad of a fully functional Rpb1 CTD array (comprising 14 consensus heptad repeats linked to the body of Rpb1 by a "rump" consisting of four degenerate heptads), we determined that: (i) Tyr1, Pro3, Ser5, and Pro6 are essential ...

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“…In yeast, Y 1 , S 2 , S 5 and S 7 have been found to be phosphorylated during transcription, while mammals in addition also phosphorylate T 4 . 1,8,9 Early in the transcription cycle, Kin28 phosphorylates the CTD on S 5 , which serves as a mark for recruitment of the mRNA capping machinery. 10 As RNAP II elongates, the levels of phosphorylated S 5 progressively decrease due to the action of the phospho-S 5 -specific phosphatases Rtr1 and Ssu72, while the phosphorylation of S 2 increases toward the 3' end of the ORF due to activity of Bur1 and Ctk1.…”

Section: The Ctd Kinases Involved In the Ctd Phosphorylation Cyclementioning

confidence: 99%

The cell cycle rallies the transcription cycle

Chymkowitch

Enserink

2013

Transcription

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Threonine-4 of mammalian RNA polymerase II CTD is targeted by Polo-like kinase 3 and required for transcriptional elongation

Cited by 127 publications

References 73 publications

Localization of RNAPII and 3′ end formation factor CstF subunits onC. elegansgenes and operons

Localization of RNAPII and 3′ end formation factor CstF subunits onC. elegansgenes and operons

Individual letters of the RNA polymerase II CTD code govern distinct gene expression programs in fission yeast

The cell cycle rallies the transcription cycle

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