mRNA Capping (Homo sapiens)

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1, 5, 7, 9310101034103nucleoplasmcytosolGTPGTF2H4 CDK7 nascent pre-mRNA transcript POLR2H GTF2H5 Cap Binding Complex(CBC)Capping complex(initial)POLR2F POLR2E POLR2E p-SUPT5H GTF2H1 GTF2H1 NCBP2 POLR2E MNAT1 GTF2H3 Nascent pre-mRNA with 5'-GMP associated with CE POLR2J GTF2H3 POLR2D GTF2F2 p-S5-POLR2A POLR2K GTF2F1 GTF2F1 POLR2G POLR2D RNA Pol II withphosphorylated CTD:CE complex withactivated GTPOLR2G CDK7 POLR2F POLR2K POLR2L POLR2B GTF2H3 NCBP2capped pre-mRNA GTF2H5 GTF2F1 ERCC2 POLR2K POLR2L GTF2H5 POLR2I POLR2K POLR2K POLR2I POLR2D DNA POLR2F GTF2H4 CDK7 ERCC2 GTF2H1 p-S5-POLR2A ERCC2 p-S5-POLR2A ERCC2 GTF2H2 CDK7 POLR2C MNAT1 GTF2H5 POLR2J ERCC3 Capping complex(hydrolyzed)template DNA:30 nt transcript hybrid GTF2H3 ERCC2 GTF2F2 CDK7 PiPOLR2G GTF2H3 cappedpre-mRNA:CBC:RNAPol II(phosphorylated)complexCDK7 RNMT POLR2F POLR2L GTF2H5 p-SUPT5H GTF2H2 RNGTT POLR2J POLR2H POLR2C MNAT1 CCNH POLR2J nascent pre-mRNAtranscriptPOLR2B p-SUPT5H template DNA:30 nt transcript hybrid GTF2H1 p-S5-POLR2A POLR2H RNGTT CDK7 POLR2E DNAPOLR2I POLR2J GTF2F1 POLR2J GTF2H4 GTF2F1 POLR2H POLR2J POLR2K DNA POLR2K GTF2H5 MNAT1 GTF2F2 CCNH GTF2H2 POLR2H POLR2F RNMTPOLR2L mRNA capping factorsCapping complex(GpppN..)POLR2E ERCC2 RNGTT POLR2B POLR2L POLR2I CCNH CCNH ERCC3 POLR2B POLR2F POLR2C GMP MNAT1 POLR2C POLR2K Pol II transcriptioncomplex with (ser5)phosphorylated CTDcontaining extrudedtranscript to +30p-SUPT5H POLR2H CCNH POLR2D POLR2B GTF2H3 Nascent pre-mRNA with hydrolysed 5'-end GTF2H4 ERCC3 POLR2K Nascent pre-mRNA with 5'-GMP dissociated from CE MNAT1 POLR2L GTF2H5 POLR2E ERCC3 GTF2H2 GTF2F2 POLR2D ERCC2 p-SUPT5HPOLR2F POLR2D POLR2H POLR2G POLR2C p-S5-POLR2A RNGTT POLR2D ERCC3 p-SUPT5H RNMT GTF2H2 POLR2E POLR2H GTF2H1 Nascent pre-mRNA with hydrolysed 5'-end POLR2B GTF2H2 GTF2H1 CDK7 GTF2H4 template DNA:30 nt transcript hybrid MNAT1 POLR2C RNMT ERCC3 POLR2G POLR2C GTF2F1 GTF2F2 NCBP1 p-S5-POLR2A GTF2H1 Capping complex(with freed 5'-GMP)RNGTT RNMT GTF2F2 POLR2I RNAPolymeraseII(phosphorylated):TFIIF:capped pre-mRNAERCC3 GTF2H3 GDPCCNH POLR2G GTF2F1 NCBP2 POLR2G POLR2F CCNH POLR2E POLR2E DNA GTF2H4 RNMT POLR2I POLR2H DNA template DNA:30 nt transcript hybrid POLR2G ERCC3 Capping complex (intermediate)CCNH POLR2E POLR2L GTF2F2 GTF2F2 MNAT1 POLR2H POLR2J template DNA:30 nt transcript hybrid POLR2C POLR2G RNMT POLR2B GTF2H4 capped pre-mRNA MNAT1 POLR2D GTF2H2 POLR2C CCNH AdoMetGTF2H5 ERCC2 CDK7 POLR2C GTF2H4 GTF2H3 POLR2B template DNA:30 nt transcript hybrid p-S5-POLR2A POLR2D RNMT CDK7 GTF2F2 RNGTT GTF2H2 GTF2F1 POLR2L POLR2I RNA Pol II withphosphorylated CTD:CE complexPOLR2I POLR2I GTF2F1 POLR2G GTF2H2 POLR2J p-S5-POLR2A p-S5-POLR2A GTF2H3 POLR2I ERCC2 POLR2L GTF2H5 GTF2F2 RNGTT CE:Pol II CTD:Spt5complexGTF2H4 POLR2K p-S5-POLR2A POLR2L GTF2H1 RNGTTPOLR2J template DNA:30 nt transcript hybrid GTF2F1 CCNH GTF2F2 POLR2I POLR2F GTF2H4 POLR2J NCBP1 NCBP1GTF2F1 POLR2B POLR2K GTF2H1 GTF2H5 RNGTT POLR2C template DNA:30 nt transcript hybrid POLR2D RNGTT POLR2E POLR2H GTF2H3 ERCC3 POLR2F POLR2F DNA ERCC2 POLR2B POLR2D AdoHcyPOLR2B TFIIHp-S5-POLR2A POLR2G MNAT1 POLR2L GTF2H1 template DNA:30 nt transcript hybrid ERCC3 GTF2H2 p-SUPT5H 2, 6, 8


Description

The 5'-ends of all eukaryotic pre-mRNAs studied thus far are converted to cap structures. The cap is thought to influence splicing of the first intron, and is bound by 'cap-binding' proteins, CBP80 and CBP20, in the nucleus. The cap is important for translation initiation, and it also interacts with the poly(A)terminus, via proteins, resulting in circularization of the mRNA to facilitate multiple rounds of translation. The cap is also important for mRNA stability, protecting it from 5' to 3' nucleases, and is required for mRNA export to the cytoplasm.
The capping reaction usually occurs very rapidly on nascent transcripts; after the synthesis of only a few nucleotides by RNA polymerase II. The capping reaction involves the conversion of the 5'-end of the nascent transcript from a triphosphate to a diphosphate by a RNA 5'-triphosphatase, followed by the addition of a guanosine monophosphate by the mRNA guanylyltransferase, to form a 5'-5'-triphosphate linkage. This cap is then methylated by 2'-O-methyltransferases.

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Bibliography

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  1. Mizumoto K, Kaziro Y.; ''Messenger RNA capping enzymes from eukaryotic cells.''; PubMed Europe PMC Scholia
  2. Rossignol M, Kolb-Cheynel I, Egly JM.; ''Substrate specificity of the cdk-activating kinase (CAK) is altered upon association with TFIIH.''; PubMed Europe PMC Scholia
  3. Glover-Cutter K, Kim S, Espinosa J, Bentley DL.; ''RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes.''; PubMed Europe PMC Scholia
  4. Narita T, Yung TM, Yamamoto J, Tsuboi Y, Tanabe H, Tanaka K, Yamaguchi Y, Handa H.; ''NELF interacts with CBC and participates in 3' end processing of replication-dependent histone mRNAs.''; PubMed Europe PMC Scholia
  5. Gonatopoulos-Pournatzis T, Cowling VH.; ''Cap-binding complex (CBC).''; PubMed Europe PMC Scholia
  6. Görnemann J, Kotovic KM, Hujer K, Neugebauer KM.; ''Cotranscriptional spliceosome assembly occurs in a stepwise fashion and requires the cap binding complex.''; PubMed Europe PMC Scholia
  7. Bentley D.; ''Coupling RNA polymerase II transcription with pre-mRNA processing.''; PubMed Europe PMC Scholia
  8. Schultz P, Fribourg S, Poterszman A, Mallouh V, Moras D, Egly JM.; ''Molecular structure of human TFIIH.''; PubMed Europe PMC Scholia
  9. Heidemann M, Hintermair C, Voß K, Eick D.; ''Dynamic phosphorylation patterns of RNA polymerase II CTD during transcription.''; PubMed Europe PMC Scholia
  10. Schoenberg DR, Maquat LE.; ''Re-capping the message.''; PubMed Europe PMC Scholia
  11. Yamada-Okabe T, Doi R, Shimmi O, Arisawa M, Yamada-Okabe H.; ''Isolation and characterization of a human cDNA for mRNA 5'-capping enzyme.''; PubMed Europe PMC Scholia
  12. Shatkin AJ, Manley JL.; ''The ends of the affair: capping and polyadenylation.''; PubMed Europe PMC Scholia
  13. Giglia-Mari G, Giglia-Mari G, Coin F, Ranish JA, Hoogstraten D, Theil A, Wijgers N, Jaspers NG, Raams A, Argentini M, van der Spek PJ, Botta E, Stefanini M, Egly JM, Aebersold R, Hoeijmakers JH, Vermeulen W.; ''A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A.''; PubMed Europe PMC Scholia
  14. Tsukamoto T, Shibagaki Y, Niikura Y, Mizumoto K.; ''Cloning and characterization of three human cDNAs encoding mRNA (guanine-7-)-methyltransferase, an mRNA cap methylase.''; PubMed Europe PMC Scholia
  15. Buratowski S.; ''Progression through the RNA polymerase II CTD cycle.''; PubMed Europe PMC Scholia
  16. Giacometti S, Benbahouche NEH, Domanski M, Robert MC, Meola N, Lubas M, Bukenborg J, Andersen JS, Schulze WM, Verheggen C, Kudla G, Jensen TH, Bertrand E.; ''Mutually Exclusive CBC-Containing Complexes Contribute to RNA Fate.''; PubMed Europe PMC Scholia
  17. Proudfoot NJ, Furger A, Dye MJ.; ''Integrating mRNA processing with transcription.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114780view16:27, 25 January 2021ReactomeTeamReactome version 75
113225view11:29, 2 November 2020ReactomeTeamReactome version 74
112446view15:39, 9 October 2020ReactomeTeamReactome version 73
101352view11:23, 1 November 2018ReactomeTeamreactome version 66
100890view20:57, 31 October 2018ReactomeTeamreactome version 65
100431view19:32, 31 October 2018ReactomeTeamreactome version 64
99980view16:15, 31 October 2018ReactomeTeamreactome version 63
99534view14:52, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99171view12:42, 31 October 2018ReactomeTeamreactome version 62
93902view13:43, 16 August 2017ReactomeTeamreactome version 61
93475view11:24, 9 August 2017ReactomeTeamreactome version 61
86572view09:21, 11 July 2016ReactomeTeamreactome version 56
83238view10:27, 18 November 2015ReactomeTeamVersion54
76815view08:03, 17 July 2014ReactomeTeamFixed remaining interactions
76519view11:45, 16 July 2014ReactomeTeamFixed remaining interactions
76140view13:57, 11 June 2014AnweshaFixed url error
76128view10:42, 11 June 2014AnweshaModified description
75852view09:50, 11 June 2014ReactomeTeamRe-fixing comment source
75552view10:34, 10 June 2014ReactomeTeamReactome 48 Update
74907view13:43, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74551view08:35, 30 April 2014ReactomeTeamReactome46
44921view10:47, 6 October 2011MartijnVanIerselOntology Term : 'transcription pathway' added !
42079view21:55, 4 March 2011MaintBotAutomatic update
39887view05:55, 21 January 2011MaintBotNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
CCNH ProteinP51946 (Uniprot-TrEMBL)
CDK7 ProteinP50613 (Uniprot-TrEMBL)
CE:Pol II CTD:Spt5 complexComplexR-HSA-77061 (Reactome) Spt5 reacts with Guanyl Transferase (GT) of the capping enzyme (CE).
Cap Binding Complex (CBC)ComplexR-HSA-77088 (Reactome)
Capping complex (GpppN..)ComplexR-HSA-77066 (Reactome)
Capping complex (hydrolyzed)ComplexR-HSA-77064 (Reactome)
Capping complex (initial)ComplexR-HSA-77063 (Reactome)
Capping complex

(with freed 5'-

GMP)		ComplexR-HSA-77067 (Reactome)
Capping complex (intermediate)ComplexR-HSA-77065 (Reactome)
DNA R-NUL-29428 (Reactome)
DNAR-NUL-29428 (Reactome)
ERCC2 ProteinP18074 (Uniprot-TrEMBL)
ERCC3 ProteinP19447 (Uniprot-TrEMBL)
GDPMetaboliteCHEBI:17552 (ChEBI)
GMP MetaboliteCHEBI:17345 (ChEBI)
GTF2F1 ProteinP35269 (Uniprot-TrEMBL)
GTF2F2 ProteinP13984 (Uniprot-TrEMBL)
GTF2H1 ProteinP32780 (Uniprot-TrEMBL)
GTF2H2 ProteinQ13888 (Uniprot-TrEMBL)
GTF2H3 ProteinQ13889 (Uniprot-TrEMBL)
GTF2H4 ProteinQ92759 (Uniprot-TrEMBL)
GTF2H5 ProteinQ6ZYL4 (Uniprot-TrEMBL)
GTPMetaboliteCHEBI:15996 (ChEBI)
MNAT1 ProteinP51948 (Uniprot-TrEMBL)
NCBP1 ProteinQ09161 (Uniprot-TrEMBL)
NCBP1ProteinQ09161 (Uniprot-TrEMBL)
NCBP2 ProteinP52298 (Uniprot-TrEMBL)
NCBP2ProteinP52298 (Uniprot-TrEMBL)
Nascent pre-mRNA with 5'-GMP associated with CE R-NUL-111344 (Reactome)
Nascent pre-mRNA with 5'-GMP dissociated from CE R-NUL-111345 (Reactome)
Nascent pre-mRNA with hydrolysed 5'-end R-NUL-111341 (Reactome)
POLR2B ProteinP30876 (Uniprot-TrEMBL)
POLR2C ProteinP19387 (Uniprot-TrEMBL)
POLR2D ProteinO15514 (Uniprot-TrEMBL)
POLR2E ProteinP19388 (Uniprot-TrEMBL)
POLR2F ProteinP61218 (Uniprot-TrEMBL)
POLR2G ProteinP62487 (Uniprot-TrEMBL)
POLR2H ProteinP52434 (Uniprot-TrEMBL)
POLR2I ProteinP36954 (Uniprot-TrEMBL)
POLR2J ProteinP52435 (Uniprot-TrEMBL)
POLR2K ProteinP53803 (Uniprot-TrEMBL)
POLR2L ProteinP62875 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
Pol II transcription

complex with (ser5) phosphorylated CTD containing extruded

transcript to +30		ComplexR-HSA-157174 (Reactome)
RNA

Polymerase II

(phosphorylated):TFIIF:capped pre-mRNA		ComplexR-HSA-113405 (Reactome)
RNA Pol II with

phosphorylated CTD: CE complex with

activated GT		ComplexR-HSA-77056 (Reactome)
RNA Pol II with

phosphorylated CTD:

CE complex		ComplexR-HSA-77053 (Reactome)
RNGTT ProteinO60942 (Uniprot-TrEMBL)
RNGTTProteinO60942 (Uniprot-TrEMBL)
RNMT ProteinO43148 (Uniprot-TrEMBL)
RNMTProteinO43148 (Uniprot-TrEMBL)
TFIIHComplexR-HSA-109634 (Reactome)
capped

pre-mRNA:CBC:RNA Pol II (phosphorylated)

complex		ComplexR-HSA-77089 (Reactome)
capped pre-mRNA R-NUL-72085 (Reactome)
mRNA capping factorsComplexR-HSA-113403 (Reactome)
nascent pre-mRNA transcriptR-NUL-72084 (Reactome)
nascent pre-mRNA transcript R-NUL-72084 (Reactome)
p-S5-POLR2A ProteinP24928 (Uniprot-TrEMBL)
p-SUPT5H ProteinO00267 (Uniprot-TrEMBL)
p-SUPT5HProteinO00267 (Uniprot-TrEMBL)
template DNA:30 nt transcript hybrid R-NUL-111260 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
AdoHcyArrowR-HSA-77090 (Reactome)
AdoMetR-HSA-77090 (Reactome)
CE:Pol II CTD:Spt5 complexArrowR-HSA-77073 (Reactome)
CE:Pol II CTD:Spt5 complexR-HSA-77077 (Reactome)
Cap Binding Complex (CBC)ArrowR-HSA-77094 (Reactome)
Cap Binding Complex (CBC)R-HSA-77095 (Reactome)
Capping complex (GpppN..)ArrowR-HSA-77083 (Reactome)
Capping complex (GpppN..)R-HSA-77085 (Reactome)
Capping complex (hydrolyzed)ArrowR-HSA-77078 (Reactome)
Capping complex (hydrolyzed)R-HSA-77081 (Reactome)
Capping complex (hydrolyzed)mim-catalysisR-HSA-77081 (Reactome)
Capping complex (initial)ArrowR-HSA-77077 (Reactome)
Capping complex (initial)R-HSA-77078 (Reactome)
Capping complex (initial)mim-catalysisR-HSA-77078 (Reactome)
Capping complex

(with freed 5'-

GMP)		ArrowR-HSA-77085 (Reactome)
Capping complex

(with freed 5'-

GMP)		R-HSA-77090 (Reactome)
Capping complex

(with freed 5'-

GMP)		mim-catalysisR-HSA-77090 (Reactome)
Capping complex (intermediate)ArrowR-HSA-77081 (Reactome)
Capping complex (intermediate)R-HSA-77083 (Reactome)
Capping complex (intermediate)mim-catalysisR-HSA-77083 (Reactome)
DNAR-HSA-77077 (Reactome)
GDPArrowR-HSA-77081 (Reactome)
GTPR-HSA-77081 (Reactome)
NCBP1R-HSA-77094 (Reactome)
NCBP2R-HSA-77094 (Reactome)
PiArrowR-HSA-77078 (Reactome)
Pol II transcription

complex with (ser5) phosphorylated CTD containing extruded

transcript to +30		R-HSA-77069 (Reactome)
R-HSA-77068 (Reactome) At the beginning of this reaction, 1 molecule of 'RNA Pol II with phosphorylated CTD: CE complex' is present. At the end of this reaction, 1 molecule of 'RNA Pol II with phosphorylated CTD: CE complex with activated GT' is present.

This reaction takes place in the 'nucleus'.

R-HSA-77069 (Reactome) At the beginning of this reaction, 1 molecule of 'mRNA capping enzyme', and 1 molecule of 'Pol II transcription complex with (ser5) phosphorylated CTD containing extruded transcript to +30' are present. At the end of this reaction, 1 molecule of 'RNA Pol II with phosphorylated CTD: CE complex' is present.

This reaction takes place in the 'nucleus'.

R-HSA-77073 (Reactome) The capping enzyme interacts with the Spt5 subunit of transcription elongation factor DSIF. This interaction may couple the capping reaction with promoter escape or elongation, thereby acting as a "checkpoint" to assure that capping has occurred before the polymerase proceeds to make the rest of the transcript.
R-HSA-77077 (Reactome) The capping enzyme binds the 5'-end of the nascent transcript soon after it is synthesized on the DNA template, and results in the formation of the capping complex along with the C-terminal domain of RNA polymerase II, and Spt5.
R-HSA-77078 (Reactome) After the capping complex is formed, the RNA triphosphatase activity of the capping enzyme hydrolyzes the 5'-end phosphate group of the nascent mRNA transcript to a diphosphate.
The RNA triphosphatase (RTP) domain of mammalian capping enzyme is a member of a superfamily of phosphatases that include the protein tyrosine phosphatases, some lipid phosphatases, and several nucleic acid phosphatases. This family uses a conserved nucleophilic cysteine residue to attack the target phosphate. A transient phospho-cysteinyl enzyme intermediate is then hydrolyzed to regenerate the enzyme active site. It should be noted that while higher eukaryotic capping enzymes use PTP-like triphosphatase domains, the yeast triphosphatases are a completely different class of enzymes. The yeast RTPs are metal-dependent phosphatases. RNA 5'-triphosphatase (RTP) catalyzed first reaction can be represented as:pppN(pN)n + GTP -> ppN(pN)n + Pi; (n=20-25)


R-HSA-77081 (Reactome) A highly conserved lysine within the guanylyltransferase (GT) site of the mRNA capping enzyme attacks the alpha-phosphate of GTP. An enzyme-GMP covalent intermediate is formed.

R-HSA-77083 (Reactome) The diphosphate 5'-end of the mRNA is joined to the GMP, releasing it from the enzyme. At this time, it is unclear how the RNA diphosphate end is transferred from the active site of the triphosphatase to the guanylyltransferase site. The covalent enzyme-GMP complex can form in the absence of RNA.
Guanylyltransferase (GT) catalyzed second reaction can be represented as:ppN(pN)n + GTP -> GpppN(pN)n + PPi


R-HSA-77085 (Reactome) GMP capped mRNA transcript dissociates from GT for further modification.
R-HSA-77090 (Reactome) In the final step of the capping reaction, the methyltransferase takes a methyl group from S-adenosyl-methionine to the N7 position of the cap guanine. N7G-methyltransferase (MT) mediated reaction can be represented as:
GpppN(pN)n + S-adenosylmethionine (Adomet) ->m7GpppN(pN)n + S-adenosylhomocysteine (Adohcy).


R-HSA-77094 (Reactome) At the beginning of this reaction, 1 molecule of 'CBP80', and 1 molecule of 'CBP20' are present. At the end of this reaction, 1 molecule of 'Cap Binding Complex (CBC)' is present.

This reaction takes place in the 'nucleus'.

R-HSA-77095 (Reactome) The cap binding complex binds to the methylated GMP cap on the nascent mRNA transcript (Gonatopoulos-Pournatzis & Cowling 2014).
RNA

Polymerase II

(phosphorylated):TFIIF:capped pre-mRNA		ArrowR-HSA-77090 (Reactome)
RNA

Polymerase II

(phosphorylated):TFIIF:capped pre-mRNA		R-HSA-77095 (Reactome)
RNA Pol II with

phosphorylated CTD: CE complex with

activated GT		ArrowR-HSA-77068 (Reactome)
RNA Pol II with

phosphorylated CTD: CE complex with

activated GT		R-HSA-77073 (Reactome)
RNA Pol II with

phosphorylated CTD:

CE complex		ArrowR-HSA-77069 (Reactome)
RNA Pol II with

phosphorylated CTD:

CE complex		R-HSA-77068 (Reactome)
RNGTTR-HSA-77069 (Reactome)
RNMTR-HSA-77073 (Reactome)
TFIIHArrowR-HSA-77090 (Reactome)
capped

pre-mRNA:CBC:RNA Pol II (phosphorylated)

complex		ArrowR-HSA-77095 (Reactome)
mRNA capping factorsArrowR-HSA-77090 (Reactome)
nascent pre-mRNA transcriptR-HSA-77077 (Reactome)
p-SUPT5HArrowR-HSA-77090 (Reactome)
p-SUPT5HR-HSA-77073 (Reactome)

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