mRNA Capping (Homo sapiens)
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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.
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.
Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=72086</div>
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- Mizumoto K, Kaziro Y.; ''Messenger RNA capping enzymes from eukaryotic cells.''; PubMed Europe PMC Scholia
- 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
- 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
- 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
- Gonatopoulos-Pournatzis T, Cowling VH.; ''Cap-binding complex (CBC).''; PubMed Europe PMC Scholia
- 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
- Bentley D.; ''Coupling RNA polymerase II transcription with pre-mRNA processing.''; PubMed Europe PMC Scholia
- Schultz P, Fribourg S, Poterszman A, Mallouh V, Moras D, Egly JM.; ''Molecular structure of human TFIIH.''; PubMed Europe PMC Scholia
- Heidemann M, Hintermair C, Voß K, Eick D.; ''Dynamic phosphorylation patterns of RNA polymerase II CTD during transcription.''; PubMed Europe PMC Scholia
- Schoenberg DR, Maquat LE.; ''Re-capping the message.''; PubMed Europe PMC Scholia
- 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
- Shatkin AJ, Manley JL.; ''The ends of the affair: capping and polyadenylation.''; PubMed Europe PMC Scholia
- 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
- 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
- Buratowski S.; ''Progression through the RNA polymerase II CTD cycle.''; PubMed Europe PMC Scholia
- 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
- Proudfoot NJ, Furger A, Dye MJ.; ''Integrating mRNA processing with transcription.''; PubMed Europe PMC Scholia
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Annotated Interactions
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| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| AdoHcy | Arrow | REACT_404 (Reactome)  | ||
| AdoMet | REACT_404 (Reactome) | |||
| CE
Pol II CTD Spt5 complex | REACT_2186 (Reactome) | |||
| Cap Binding Complex | REACT_687 (Reactome) | |||
| Capping complex | Arrow | REACT_1580 (Reactome) | ||
| Capping complex | mim-catalysis | REACT_1968 (Reactome) | ||
| Capping complex | Arrow | REACT_1368 (Reactome) | ||
| Capping complex | REACT_1580 (Reactome) | |||
| Capping complex | REACT_404 (Reactome) | |||
| Capping complex | mim-catalysis | REACT_1368 (Reactome) | ||
| Capping complex | mim-catalysis | REACT_1580 (Reactome) | ||
| Capping complex | mim-catalysis | REACT_404 (Reactome) | ||
| DNA | REACT_2186 (Reactome) | |||
| GDP | Arrow | REACT_1580 (Reactome) | ||
| GTP | REACT_1580 (Reactome) | |||
| Pi | Arrow | REACT_1368 (Reactome) | ||
| REACT_1368 (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) | |||
| REACT_1580 (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. | |||
| REACT_1968 (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 | |||
| REACT_2093 (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'. | |||
| REACT_2186 (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. | |||
| REACT_2233 (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'. | |||
| REACT_404 (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). | |||
| REACT_423 (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. | |||
| REACT_687 (Reactome) | The cap binding complex binds to the methylated GMP cap on the nascent mRNA transcript. | |||
| REACT_703 (Reactome) | GMP capped mRNA transcript dissociates from GT for further modification. | |||
| REACT_893 (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'. | |||
| RNA Polymerase II | Arrow | REACT_404 (Reactome) | ||
| RNA Polymerase II | REACT_687 (Reactome) | |||
| TFIIH | Arrow | REACT_404 (Reactome) | ||
| mRNA capping factors | Arrow | REACT_404 (Reactome) | ||
| nascent pre-mRNA transcript | REACT_2186 (Reactome) | |||
| p-SUPT5H | Arrow | REACT_404 (Reactome) |
