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Information on EC 2.7.11.23 - [RNA-polymerase]-subunit kinase and Organism(s) Mus musculus
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2.7.11.23 [RNA-polymerase]-subunit kinaseIUBMB Comments
The enzyme appears to be distinct from other protein kinases. It brings about multiple phosphorylations of the unique C-terminal repeat domain of the largest subunit of eukaryotic DNA-directed RNA polymerase (EC 2.7.7.6). The enzyme does not phosphorylate casein, phosvitin or histone.
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Word Map
- 2.7.11.23
- cyclin
- strand
- chromatin
- histone
-
non-homologous
-
cyclin-dependent
-
end-joining
-
radiosensitivity
-
transactivation
- helicase
-
checkpoint
-
radiation-induced
- pigmentosum
- xeroderma
- ataxia
- telangiectasia
- h2ax
-
dna-damaging
- tfiie
- wortmannin
-
preinitiation
- ataxia-telangiectasia
-
rejoin
- cak
-
cockayne
- brd4
-
pausing
-
snrnp
- tbp
- rad3-related
-
cdk-activating
-
bromodomains
- xrcc4
-
pikks
-
promoter-proximal
- rad51
-
paused
-
ir-induced
-
end-binding
- drb
- flavopiridol
-
artemis
-
unrepaired
-
gammah2ax
-
transcription-coupled
-
t-loop
-
atm-dependent
-
dsb-induced
- rpb1
-
atm-deficient
- medicine
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Archaea, Bacteria
Reaction Schemes
Synonyms
dna-pk, tfiih, p-tefb, dna-dependent protein kinase, positive transcription elongation factor b, kin28, ctd kinase, srb10, ctdk-i, tfiih kinase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
C-terminal repeat domain kinase
-
-
-
-
CTD kinase
-
-
-
-
kinase, ribonucleate nucleotidyltransferase II C-terminal domain (phosphorylating)
-
-
-
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kinase, ribonucleate nucleotidyltransferase isozyme II IIa subunit (phosphorylating)
-
-
-
-
RNA polymerase II CTD kinase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:[DNA-directed RNA polymerase] phosphotransferase
The enzyme appears to be distinct from other protein kinases. It brings about multiple phosphorylations of the unique C-terminal repeat domain of the largest subunit of eukaryotic DNA-directed RNA polymerase (EC 2.7.7.6). The enzyme does not phosphorylate casein, phosvitin or histone.
CAS REGISTRY NUMBER
COMMENTARY
122097-00-1
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + chicken myosin regulatory light-chain
ADP + chicken myosin regulatory light-chain phosphate
-
-
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
additional information
?
-
BRD4 autophosphorylation in an in vitro kinase reaction. Phoshorylation site determination with RNA Pol II CTD using a series of GST-CTD fusions with 25- or 16-heptad repeats bearing alanine substitutions in every heptad at Ser2, Ser5, Ser7, or Thr4 as substrates
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
-
-
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
-
no substrates are dTTP and AMP-PNP
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
-
no substrates are the RNA polymerases II of Drosophila melanogaster and yeast
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
-
no substrates are CTP and UTP
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
-
presumably obligate part of transcription process
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
-
the CTD is essential for viability, although mutants with deletions that remove approximately half of the repeats are still viable
-
-
?
ATP + [DNA-directed RNA polymerase]
ADP + phospho-[DNA-directed RNA polymerase]
phosphorylation at Ser2 by BRD4 kinase. BRD4 phosphorylates the Pol II CTD in in vitro transcription reactions
-
-
?
ATP + [DNA-directed RNA polymerase]
ADP + phospho-[DNA-directed RNA polymerase]
BRD4 phosphorylates CTD proteins containing the consensus sequence and Ala substitutions at Ser5 and Ser7, but it does not phosphorylate Ser2 substitutions either alone or combined with Ser5. BRD4 phosphorylates all consensus CTD heptad repeats. Assay substrate is recombinant full-length human GST-tagged CTD
-
-
?
ATP + [RNA polymerase II]
ADP + phospho-[RNA polymerase II]
cyclin-dependent kinase 9 (CDK9) is a subunit of the positive transcription elongation factor b (P-TEFb) complex that regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
ATP + [DNA-directed RNA polymerase]
ADP + phospho-[DNA-directed RNA polymerase]
phosphorylation at Ser2 by BRD4 kinase. BRD4 phosphorylates the Pol II CTD in in vitro transcription reactions
-
-
?
ATP + [RNA polymerase II]
ADP + phospho-[RNA polymerase II]
cyclin-dependent kinase 9 (CDK9) is a subunit of the positive transcription elongation factor b (P-TEFb) complex that regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
-
-
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
-
presumably obligate part of transcription process
-
-
?
ATP + [DNA-directed eukaryotic RNA polymerase II subunit IIa]
ADP + phospho-[DNA-directed RNA polymerase II subunit IIa]
-
the CTD is essential for viability, although mutants with deletions that remove approximately half of the repeats are still viable
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
additional information
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide
i.e. CPI203, phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin
(S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate
i.e. JQ1
GST-CTD
-
overexpression of this fragment inhibits tyrosine phosphorylation of RNAP II in vivo
-
additional information
BRD4 phosphorylation of the CTD is not affected by either flavopiridol or roscovitine. Inhibitors of DNA-PK and MAP (Erk1/2) CTD kinases as well as common broad spectrum kinase inhibitors have no effect on BRD4
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000085
[DNA-directed RNA polymerase]
recombinant enzyme, pH 6.0-7.5, temperature not specified in the publication
0.01
ATP
recombinant enzyme, pH 6.0-7.5, temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.03 - 0.099
(S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide
Mus musculus
pH 6.0-7.5, temperature not specified in the publication
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug target
the highly selective CDK9/P-TEFb inhibitor BAY1143572 shows strong potential as a treatment of adult T-cell leukemia/lymphoma (ATL)
malfunction
metabolism
cyclin-dependent kinase 9 (CDK9) is a subunit of the positive transcription elongation factor b (P-TEFb) complex that regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II
physiological function
the bromodomain protein BRD4 is an atypical kinase that phosphorylates serine 2 of the RNA polymerase II C-terminal domain directly both in vitro and in vivo under conditions where other CTD kinases are inactive. It is involved in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus. It is a regulator of eukaryotic transcription
malfunction
loss of the enzyme BRD4 is associated with metastatic breast cancer. BRD4 knockdown suppresses global transcription in murine embryonic fibroblasts, overview
malfunction
the deregulation of CDK9/PTEFb has important implications for many cancer types
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CDK1_MOUSE
297
0
34107
Swiss-Prot
other Location (Reliability: 1)
CDK7_MOUSE
346
0
38968
Swiss-Prot
other Location (Reliability: 2)
CDK8_MOUSE
464
0
53210
Swiss-Prot
other Location (Reliability: 1)
CDK9_MOUSE
372
0
42762
Swiss-Prot
other Location (Reliability: 1)
CDK12_MOUSE
1484
0
163681
Swiss-Prot
other Location (Reliability: 1)
CDK13_MOUSE
1511
0
164553
Swiss-Prot
other Location (Reliability: 2)
Q8CAC4_MOUSE
252
0
28596
TrEMBL
other Location (Reliability: 2)
Q3THG5_MOUSE
346
0
38968
TrEMBL
other Location (Reliability: 2)
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
enzymes from mouse consist of 2 components each: cdc2/p58: a cdc2 kinase (p34) and a p58 subunit, cdc2/p62: a cdc2 kinase and a p62 subunit (cyclin B), the latter is also called M phase-specific histone H1 kinase
additional information
-
enzymes from mouse consist of 2 components each: cdc2/p58: a cdc2 kinase (p34) and a p58 subunit, cdc2/p62: a cdc2 kinase and a p62 subunit (cyclin B), the latter is also called M phase-specific histone H1 kinase
additional information
BRD4 domain mapping by mass spectrometry, comparison of kinase subdomain architecture and organization of eukaryotic protein kinases and atypical protein kinases, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
recombinant BRD4, purified from insect SF9 cells, autophosphorylates, and recombinant BRD4 purified from Escherichia coli also autophosphorylates
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
purified mouse enzymes are rather unstable with a half-life of several days, bovine serum albumin does not stabilize
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant BRD4 from Escherichia coli and from Spodoptera frugiperda Sf9 insect cells
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant expression of BRD4 in Escherichia coli and in Spodoptera frugiperda Sf9 insect cells, in vitro transcription was done using HeLa nuclear extract and the MHC I gene promoter in the presence of ATP
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
the bromodomain protein, BRD4, is a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitts lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease. Loss of the enzyme BRD4 is a prognostic signature for metastatic breast cancer
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Cisek, L.J.; Corden, J.L.
Purification of protein kinases that phosphorylate the repetitive carboxyl-terminal domain of eukaryotic RNA polymerase II
Methods Enzymol.
200
301-325
1991
Saccharomyces cerevisiae, Homo sapiens, Mus musculus, Triticum aestivum
Feuerstein, N.
Phosphorylation of numatrin and other nuclear proteins by cdc2 containing CTD kinase cdc2/p58
J. Biol. Chem.
266
16200-16206
1991
Mus musculus
Baskaran, R.; Escobar, S.R.; Wang, J.Y.
Nuclear c-Abl is a COOH-terminal repeated domain (CTD)-tyrosine (CTD)-tyrosine kinase-specific for the mammalian RNA polymerase II: possible role in transcription elongation
Cell Growth Differ.
10
387-396
1999
Mus musculus
Prelich, G.
RNA polymerase II carboxy-terminal domain kinases: emerging clues to their function
Eukaryot. Cell
1
153-162
2002
Saccharomyces cerevisiae, Drosophila sp. (in: flies), Mus musculus
Devaiah, B.N.; Lewis, B.A.; Cherman, N.; Hewitt, M.C.; Albrecht, B.K.; Robey, P.G.; Ozato, K.; Sims, R.J.; Singer, D.S.
BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain
Proc. Natl. Acad. Sci. USA
109
6927-6932
2012
Mus musculus (Q9ESU6)
Narita, T.; Ishida, T.; Ito, A.; Masaki, A.; Kinoshita, S.; Suzuki, S.; Takino, H.; Yoshida, T.; Ri, M.; Kusumoto, S.; Komatsu, H.; Imada, K.; Tanaka, Y.; Takaori-Kondo, A.; Inagaki, H.; Scholz, A.; Lienau, P.; Kuroda, T.; Ueda, R.; Iida, S.
Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma
Blood
130
1114-1124
2017
Mus musculus (Q99J95)
EXTERNAL LINKS (specific for EC-Number 2.7.11.23)
Transporter Classification Database (TCDB): 1.I.1.1.3
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