mRNA Capping (Homo sapiens)

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ArcPathVisio Brace Ellipse EndoplasmicReticulum GolgiApparatus HexagonPathVisio MimDegradation Mitochondria Octagon PentagonPathVisio Rectangle RoundedRectangle SarcoplasmicReticulum TriangleEquilateralEast TrianglePathVisio none nucleoplasmcytosolCapping complex (intermediate)p-SUPT5HNCBP1Capping complex(initial)TFIIHAdoMetRNA Pol II withphosphorylated CTD:CE complexCapping complex(hydrolyzed)Capping complex(GpppN..)PiCapping complex(with freed 5'-GMP)nascent pre-mRNAtranscriptRNAPolymeraseII(phosphorylated):TFIIF:capped pre-mRNANCBP2AdoHcyRNMTGDPDNACap Binding Complex(CBC)RNGTTRNA Pol II withphosphorylated CTD:CE complex withactivated GTPol II transcriptioncomplex with (ser5)phosphorylated CTDcontaining extrudedtranscript to +30GTPmRNA capping factorscappedpre-mRNA:CBC:RNAPol II(phosphorylated)complexCE:Pol II CTD:Spt5complexCDK7ERCC3ERCC2GTF2H2GTF2H4MNAT1GTF2H3GTF2H1CCNHGTF2H5RNGTTRNMTERCC3Nascent pre-mRNA with 5'-GMP dissociated from CEERCC2POLR2BPOLR2JPOLR2GPOLR2LCCNHRNMTPOLR2HPOLR2IGTF2H2POLR2EGTF2H1DNAPOLR2KCDK7GTF2F1POLR2CPOLR2FPOLR2DGTF2H5MNAT1RNGTTGTF2F2p-SUPT5HGTF2H3template DNA:30 nt transcript hybridGTF2H4p-S5-POLR2ANCBP2NCBP1POLR2CPOLR2JRNGTTCDK7POLR2Ep-S5-POLR2APOLR2BGTF2F1POLR2ICCNHGTF2H2POLR2LRNMTGTF2H3Nascent pre-mRNA with hydrolysed 5'-endGTF2H5ERCC3POLR2GERCC2DNAMNAT1GTF2H1POLR2HGTF2H4POLR2Ftemplate DNA:30 nt transcript hybridPOLR2DPOLR2KGTF2F2p-SUPT5HGTF2F2POLR2CPOLR2Bcapped pre-mRNAPOLR2DPOLR2GPOLR2FPOLR2EPOLR2LPOLR2IPOLR2KPOLR2JGTF2F1p-S5-POLR2APOLR2HRNMTPOLR2FERCC2GTF2H5POLR2LGTF2H2GTF2F2nascent pre-mRNA transcriptPOLR2EPOLR2DGTF2H3POLR2HGTF2H4POLR2Ctemplate DNA:30 nt transcript hybridDNACDK7POLR2IPOLR2Bp-SUPT5Hp-S5-POLR2AMNAT1POLR2GCCNHPOLR2KGTF2F1POLR2JRNGTTERCC3GTF2H1POLR2JGTF2H2POLR2CERCC3POLR2DCDK7CCNHGTF2H5POLR2LPOLR2KGTF2H3GTF2F2GTF2H1GTF2F1template DNA:30 nt transcript hybridPOLR2HPOLR2IPOLR2Ep-S5-POLR2APOLR2GMNAT1POLR2BGTF2H4POLR2FERCC2POLR2CGTF2H4ERCC3POLR2FGTF2F2POLR2BPOLR2GPOLR2IGTF2H2GTF2F1MNAT1POLR2EGTF2H1CCNHPOLR2Jp-S5-POLR2AGTF2H5RNGTTPOLR2LPOLR2HPOLR2DGTF2H3CDK7ERCC2POLR2Ktemplate DNA:30 nt transcript hybridPOLR2DGTF2H2GTF2F1ERCC2p-S5-POLR2APOLR2GPOLR2JPOLR2LCDK7GTF2H5GTF2H3POLR2KPOLR2ECCNHPOLR2IPOLR2CMNAT1RNMTGTF2H4ERCC3p-SUPT5HPOLR2HPOLR2BGTF2H1POLR2Ftemplate DNA:30 nt transcript hybridRNGTTGTF2F2POLR2ECCNHERCC3POLR2KDNANascent pre-mRNA with hydrolysed 5'-endRNGTTPOLR2JPOLR2LGTF2H4RNMTGTF2H2CDK7GMPPOLR2FPOLR2CPOLR2GGTF2H1POLR2BPOLR2IGTF2H3ERCC2MNAT1POLR2Dp-SUPT5HGTF2H5template DNA:30 nt transcript hybridGTF2F1POLR2Hp-S5-POLR2AGTF2F2GTF2H3POLR2GPOLR2EPOLR2KGTF2H1POLR2CPOLR2LPOLR2BDNAPOLR2DGTF2F1Nascent pre-mRNA with 5'-GMP associated with CEtemplate DNA:30 nt transcript hybridERCC3p-SUPT5HPOLR2HPOLR2FGTF2F2GTF2H2MNAT1POLR2IGTF2H5RNMTCDK7GTF2H4p-S5-POLR2APOLR2JERCC2RNGTTCCNHtemplate DNA:30 nt transcript hybridPOLR2Gp-S5-POLR2AERCC3GTF2H5GTF2H1POLR2DPOLR2EPOLR2JPOLR2HGTF2F1POLR2IGTF2H3CCNHPOLR2LPOLR2CGTF2H4ERCC2MNAT1POLR2FGTF2H2POLR2BGTF2F2CDK7RNGTTPOLR2KPOLR2IPOLR2LPOLR2HGTF2F1POLR2FPOLR2Bp-S5-POLR2APOLR2Dcapped pre-mRNANCBP1POLR2EPOLR2GPOLR2KPOLR2JNCBP2GTF2F2POLR2CName: mRNA CappingOrganism: Homo sapiens


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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Pathway is converted from Reactome ID: 72086
Reactome-version 
Reactome version: 75

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Ontology Terms

Pathway Ontology : classic metabolic pathway
 

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
114780
Reactome
view16:27, 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...
Name  ↓Type  ↓Database reference  ↓Comment  ↓
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-ALL-29428 (Reactome)
DNAR-ALL-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-ALL-111344 (Reactome)
Nascent pre-mRNA with 5'-GMP dissociated from CE R-ALL-111345 (Reactome)
Nascent pre-mRNA with hydrolysed 5'-end R-ALL-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:43474 (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-ALL-72085 (Reactome)
mRNA capping factorsComplexR-HSA-113403 (Reactome)
nascent pre-mRNA transcriptR-ALL-72084 (Reactome)
nascent pre-mRNA transcript R-ALL-72084 (Reactome)
p-S5-POLR2A ProteinP24928 (Uniprot-TrEMBL)
p-SUPT5H ProteinO00267 (Uniprot-TrEMBL)
p-SUPT5HProteinO00267 (Uniprot-TrEMBL)
template DNA:30 nt transcript hybrid R-ALL-111260 (Reactome)

Annotated Interactions

View all...
Source  ↓Target  ↓Type  ↓Database reference  ↓Comment  ↓
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 (Gonatopoulos-Pournatzis et al.2011).
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 (Heidemann et al. 2013, Buratowski 2009, Schoenberg and Maquat 2009).
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

(Yamada-Okabe et al. 1998).

R-HSA-77085 (Reactome) GMP capped mRNA transcript dissociates from GT for further modification (Yamada-Okabe et al. 1998).
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 (Glover-Cutter et al., 2008, Görnemann et al., 2005, Narita et al., 2007). 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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