CTD Phosphorylation

Main Page:CTD Phosphorylation

Introduction

The C-terminal domain (CTD) of RNA polymerase II's largest subunit undergoes dynamic phosphorylation during transcription, and the different phosphorylation patterns that predominate at each stage of transcription recruit the appropriate set of mRNA-processing and histone-modifying factors. The CTD has multiple phosphorylation sites, with up to five potential phosphorylation sites in a consensus heptapeptide repeat (Y1, S2, T4, S5, S7). In vivo phosphorylation occurs mainly on serine residues. The hyperphosphorylated form of the mammalian CTD has on average 1 phosphate/repeat, although the number of phosphates on the CTD at any point of the transcription cycle has not yet been determined. This complex phosphorylation patterns are regulated by quite a few phosphatases and kinases. Below is the list of known phosphatases and kinases involved in CTD phosphorylation [1].

Phosphatases

Mammals	Yeast	Group	Family	Substrate	Stage	Evolution (from yeast to human)	Note
FCP1	FCP1	HAD	FCP	pSer2, pThr4 [2]	To Recycling	From yeast to human
SCP	SCP	HAD	FCP	pSer5	To cleavage, polyA and termination	From yeast to human	The function toward pSer5 of one of its member, SCP1, has been verified in mammals, but not in yeast, yet.
SSU72	SSU72	CC2	SSU72	pSer5	To cleavage, polyA and termination	From yeast to human	1) Its function toward pSer5 has been verified in yeast, but not mammals. 2) Unlike other phosphatases, it has a fold similar to LMWPTP rather than HAD.
HSPC129	N/A	HAD	FCP	?	?	From Monosiga to human but lost in fly	1) In vitro activity toward CTD. 2) HSPC129 was divergent from SCP family.
UBLCP1	N/A	HAD	SCP	?	?	From anemone to human but lost in nematode	1) In vitro activity toward CTD.
?	N/A	?	?	pSer7	?	?	Observed phosphorylated pSer7, but the phosphatase and kinase are unknown.

Kinases

Mammals	Yeast	Group	Family	Subfamily	Substrate	Stage	Evolution	Note
CDK7	KIN28	CMGC	CDK	CDK7	Ser5	To initiation	From yeast to human but lost in Monosiga?	1) CDK7 is a component of transcription factor TFIIH. 2) KinBase shows it is absent from Monosiga.
CDK9	Bur1	CMGC	CDK	CDK9	Ser2	To elongation	From yeast to human but lost in Monosiga?	1) CDK9 is the catalytic subunit of the positive transcription elongation factor (P-TEF)b complex. 2) KinBase shows it is absent from Monosiga.
CRK7	CTK1	CMGC	CDK	CRK7	Ser2	To elongation	From Giardia to human but lost in Tetrahymena	It has been verified in yeast, but not in mammals.
CDK8	CDK8	CMGC	CDK	CDK8	Ser2 and Ser5	In the pool of pol II?	From yeast to human
CDC2	CDK1	CMGC	CDK	CDC2	Ser2 and Ser5	In the pool of pol II?	From Giardia to human	In KInbase, conserved in yeast in the tree, but absent in the hits.
ERK1/2	FUS3, KSS1, SLT2, SMK1, YKL161C	CMGC	MAPK	ERK1	Ser5	In the pool of pol II?	From Monosiga to human	Many yeast proteins in this subfamily of extracellular signal-related kinase 1/2 (ERK1 in KinBase).
?	?	?	?	?	Ser7	?	?	?

References

1. Buratowski S. Progression through the RNA polymerase II CTD cycle. Mol Cell. 2009 Nov 25;36(4):541-6. DOI:10.1016/j.molcel.2009.10.019 |
2. Hsin JP, Xiang K, and Manley JL. Function and control of RNA polymerase II C-terminal domain phosphorylation in vertebrate transcription and RNA processing. Mol Cell Biol. 2014 Jul;34(13):2488-98. DOI:10.1128/MCB.00181-14 |
3. Akhtar MS, Heidemann M, Tietjen JR, Zhang DW, Chapman RD, Eick D, and Ansari AZ. TFIIH kinase places bivalent marks on the carboxy-terminal domain of RNA polymerase II. Mol Cell. 2009 May 15;34(3):387-93. DOI:10.1016/j.molcel.2009.04.016 |
4. Tietjen JR, Zhang DW, Rodríguez-Molina JB, White BE, Akhtar MS, Heidemann M, Li X, Chapman RD, Shokat K, Keles S, Eick D, and Ansari AZ. Chemical-genomic dissection of the CTD code. Nat Struct Mol Biol. 2010 Sep;17(9):1154-61. DOI:10.1038/nsmb.1900 |
5. Kim H, Erickson B, Luo W, Seward D, Graber JH, Pollock DD, Megee PC, and Bentley DL. Gene-specific RNA polymerase II phosphorylation and the CTD code. Nat Struct Mol Biol. 2010 Oct;17(10):1279-86. DOI:10.1038/nsmb.1913 |
6. Yang XJ. Multisite protein modification and intramolecular signaling. Oncogene. 2005 Mar 3;24(10):1653-62. DOI:10.1038/sj.onc.1208173 |
7. Chapman RD, Heidemann M, Hintermair C, and Eick D. Molecular evolution of the RNA polymerase II CTD. Trends Genet. 2008 Jun;24(6):289-96. DOI:10.1016/j.tig.2008.03.010 |
8. Stiller JW and Hall BD. Evolution of the RNA polymerase II C-terminal domain. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6091-6. DOI:10.1073/pnas.082646199 |
9. Egloff S and Murphy S. Cracking the RNA polymerase II CTD code. Trends Genet. 2008 Jun;24(6):280-8. DOI:10.1016/j.tig.2008.03.008 |