Processing of Capped Intronless Pre-mRNA (Homo sapiens)

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1, 3, 4, 6, 72CPSF Mature Intronless transcript derived Histone mRNASLBPCBP80CBP20 U7 snRNPZNF473 CPSF Capped Intronless Histone pre-mRNACBC complex CPSFcapped intronless pre-mRNACBC complex Cap Binding Complex U7 snRNP-specific Sm core complex Cap Binding Complex capped intronless pre-mRNACBC complex Capped Intronless Histone pre-mRNACBP80CBP20SLBP Capped Intronless Histone pre-mRNACBP80CBP20SLBPZFP100 Complex Capped Intronless Histone pre-mRNACBC complex CPSF CPSF Cap Binding Complex U7 snRNP-specific Sm core complex U7 snRNP-specific Sm core complex CstF U7 snRNPZNF473 CstFCPSFcapped intronless pre-mRNACBC complex U7 snRNPZNF473 cytosolMature intronless derived mRNA complex CF I Cap Binding Complex CstF CPSFcapped intronless pre-mRNACBC complex CstF Capped Intronless Histone pre-mRNACBC complex Capped Intronless Histone pre-mRNACBC complex upstream mRNA fragmentCPSFPAPPABPN1 complex CF II CPSF Cap Binding Complex intronless pre-mRNA cleavage complex CPSFcapped intronless pre-mRNACBC complex capped intronless pre-mRNACBC complex CF I capped intronless pre-mRNACBC complex capped intronless pre-mRNACBC complex CPSF Cap Binding Complex CF II CstFCPSFcapped intronless pre-mRNACBC complex nucleoplasmCapped Intronless Histone pre-mRNACBP80CBP20SLBP Capped Intronless Histone pre-mRNACBCZFP100 Complex Mature intronless transcript derived Histone pre-mRNACBC complex CSTF3 SNRPG NCBP1 LSM11 SNRPD3 CPSF2 CSTF1 ATPLSM10 NCBP1 NCBP2 CPSFcapped intronless pre-mRNACBC complexNUDT21 CPSF3 SNRPE Mature intronless derived mRNA complexMature intronless transcript derived Histone pre-mRNACBC complexCPSF7 SNRPF PCF11 CPSF1 ZNF473 CPSFCPSF1 Capped Intronless Histone pre-mRNACBC complexCF INCBP1 NCBP1 SLBP CPSF2 intronless pre-mRNA cleavage complexCPSF2 NCBP2 LSM11 NCBP2 NCBP1 PABPN1 NUDT21 LSM10 CstFCPSFcapped intronless pre-mRNACBC complexNCBP2 PABPN1 U7 snRNPZNF473CSTF1 CPSF1 SNRPG NCBP1 LSM10 SLBP NCBP2 CPSF3 SNRPE CLP1 CPSF2 NCBP1 CPSF2 Capped Intronless Histone pre-mRNACBCZFP100 ComplexCstFPABPN1NCBP2 CPSF1 NCBP2 CSTF2Capped Intronless Histone pre-mRNACBP80CBP20SLBPZFP100 Complexdownstream intronless mRNA fragmentMature Intronless transcript derived Histone mRNASLBPCBP80CBP20SLBPNCBP2 SNRPF capped intronless pre-mRNACBC complexupstream mRNA fragmentCPSFPAPPABPN1 complexCPSF3 CSTF1 SNRPF SNRPB NCBP2 NCBP2 SLBP CPSF3 SNRPD3 SNRPE CSTF3 NCBP1 NCBP1 SNRPB NCBP1 NCBP2 SNRPG CLP1 PCF11 CPSF3 NCBP1 PAPOLAPAPOLACPSF3 NCBP1 CPSF7 LSM11 PAPOLACPSF1 ZNF473 CSTF3 CSTF2ZNF473 CSTF2SNRPD3 CPSF2 CPSF1 Capped Intronless Histone pre-mRNACBP80CBP20SLBPCF IINCBP2 SNRPB 5


Description

Co-transcriptional pre-mRNA splicing is not obligatory. Pre-mRNA splicing begins co-transcriptionally and often continues post-transcriptionally. Human genes contain an average of nine introns per gene, which cannot serve as splicing substrates until both 5' and 3' ends of each intron are synthesized. Thus the time that it takes for pol II to synthesize each intron defines a minimal time and distance along the gene in which splicing factors can be recruited. The time that it takes for pol II to reach the end of the gene defines the maximal time in which splicing could occur co-transcriptionally. Thus, the kinetics of transcription can affect the kinetics of splicing.
There are two classes of intronless pre-mRNAs (mRNAs expressed from genes that lack introns). The first class encodes the replication dependent histone mRNAs. These mRNAs have unique 3' ends that do not have a polyA tail. The replication dependent histone mRNAs in all metazoans, as well as Chlamydomonas and Volvox fall into this class.

The second class of mRNAs end in polyA tails, which are formed by a mechanism similar to that which poly-adenylate pre-mRNAs containing introns. In the intronless genes there is a different method of replacing the 3' splice site that activates polyadenylation. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=75067</div>

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Bibliography

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  1. Schönemann L, Kühn U, Martin G, Schäfer P, Gruber AR, Keller W, Zavolan M, Wahle E.; ''Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33.''; PubMed Europe PMC Scholia
  2. Yao C, Choi EA, Weng L, Xie X, Wan J, Xing Y, Moresco JJ, Tu PG, Yates JR, Shi Y.; ''Overlapping and distinct functions of CstF64 and CstF64τ in mammalian mRNA 3' processing.''; PubMed Europe PMC Scholia
  3. Takagaki Y, Manley JL.; ''Complex protein interactions within the human polyadenylation machinery identify a novel component.''; PubMed Europe PMC Scholia
  4. Shi Y, Di Giammartino DC, Taylor D, Sarkeshik A, Rice WJ, Yates JR, Frank J, Manley JL.; ''Molecular architecture of the human pre-mRNA 3' processing complex.''; PubMed Europe PMC Scholia
  5. Martin F, Schaller A, Eglite S, Schümperli D, Müller B.; ''The gene for histone RNA hairpin binding protein is located on human chromosome 4 and encodes a novel type of RNA binding protein.''; PubMed Europe PMC Scholia
  6. Kaufmann I, Martin G, Friedlein A, Langen H, Keller W.; ''Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114657view16:12, 25 January 2021ReactomeTeamReactome version 75
113105view11:16, 2 November 2020ReactomeTeamReactome version 74
112339view15:26, 9 October 2020ReactomeTeamReactome version 73
101239view11:13, 1 November 2018ReactomeTeamreactome version 66
100778view20:40, 31 October 2018ReactomeTeamreactome version 65
100321view19:17, 31 October 2018ReactomeTeamreactome version 64
99866view16:00, 31 October 2018ReactomeTeamreactome version 63
99423view14:36, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99106view12:39, 31 October 2018ReactomeTeamreactome version 62
93946view13:46, 16 August 2017ReactomeTeamreactome version 61
93539view11:26, 9 August 2017ReactomeTeamreactome version 61
88116view10:07, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86637view09:22, 11 July 2016ReactomeTeamreactome version 56
83073view09:53, 18 November 2015ReactomeTeamVersion54
81390view12:55, 21 August 2015ReactomeTeamVersion53
76858view08:13, 17 July 2014ReactomeTeamFixed remaining interactions
76563view11:54, 16 July 2014ReactomeTeamFixed remaining interactions
75896view09:55, 11 June 2014ReactomeTeamRe-fixing comment source
75596view10:44, 10 June 2014ReactomeTeamReactome 48 Update
74951view13:47, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74595view08:38, 30 April 2014ReactomeTeamReactome46
42106view21:57, 4 March 2011MaintBotAutomatic update
39916view05:56, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ATPMetaboliteCHEBI:15422 (ChEBI)
CF IIComplexREACT_3772 (Reactome)
CF IComplexREACT_4896 (Reactome)
CLP1 ProteinQ92989 (Uniprot-TrEMBL)
CPSF

capped intronless pre-mRNA

CBC complex		ComplexREACT_3837 (Reactome)
CPSF1 ProteinQ10570 (Uniprot-TrEMBL)
CPSF2 ProteinQ9P2I0 (Uniprot-TrEMBL)
CPSF3 ProteinQ9UKF6 (Uniprot-TrEMBL)
CPSF7 ProteinQ8N684 (Uniprot-TrEMBL)
CPSFComplexREACT_4530 (Reactome)
CSTF1 ProteinQ05048 (Uniprot-TrEMBL)
CSTF2ProteinP33240 (Uniprot-TrEMBL)
CSTF3 ProteinQ12996 (Uniprot-TrEMBL)
Capped Intronless Histone pre-mRNA

CBC

ZFP100 Complex		ComplexREACT_5338 (Reactome)
Capped Intronless Histone pre-mRNA CBC complexComplexREACT_3840 (Reactome)
Capped Intronless Histone pre-mRNA

CBP80 CBP20 SLBP

ZFP100 Complex		ComplexREACT_3667 (Reactome)
Capped Intronless Histone pre-mRNA

CBP80 CBP20

SLBP		ComplexREACT_3458 (Reactome)
CstF

CPSF capped intronless pre-mRNA

CBC complex		ComplexREACT_3025 (Reactome)
CstFComplexREACT_3503 (Reactome)
LSM10 ProteinQ969L4 (Uniprot-TrEMBL)
LSM11 ProteinP83369 (Uniprot-TrEMBL)
Mature Intronless transcript derived Histone mRNA

SLBP CBP80

CBP20		ComplexREACT_3802 (Reactome)
Mature intronless derived mRNA complexComplexREACT_4047 (Reactome)
Mature intronless transcript derived Histone pre-mRNA CBC complexComplexREACT_5592 (Reactome)
NCBP1 ProteinQ09161 (Uniprot-TrEMBL)
NCBP2 ProteinP52298 (Uniprot-TrEMBL)
NUDT21 ProteinO43809 (Uniprot-TrEMBL)
PABPN1 ProteinQ86U42 (Uniprot-TrEMBL)
PABPN1ProteinQ86U42 (Uniprot-TrEMBL)
PAPOLAProteinP51003 (Uniprot-TrEMBL)
PCF11 ProteinO94913 (Uniprot-TrEMBL)
SLBP ProteinQ14493 (Uniprot-TrEMBL)
SLBPProteinQ14493 (Uniprot-TrEMBL)
SNRPB ProteinP14678 (Uniprot-TrEMBL)
SNRPD3 ProteinP62318 (Uniprot-TrEMBL)
SNRPE ProteinP62304 (Uniprot-TrEMBL)
SNRPF ProteinP62306 (Uniprot-TrEMBL)
SNRPG ProteinP62308 (Uniprot-TrEMBL)
U7 snRNP ZNF473ComplexREACT_5001 (Reactome)
ZNF473 ProteinQ8WTR7 (Uniprot-TrEMBL)
capped intronless pre-mRNA CBC complexComplexREACT_3948 (Reactome)
downstream intronless mRNA fragmentREACT_3064 (Reactome)
intronless pre-mRNA cleavage complexComplexREACT_3895 (Reactome)
upstream mRNA fragment

CPSF PAP

PABPN1 complex		ComplexREACT_3436 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ATPREACT_1724 (Reactome)
CF IArrowREACT_45 (Reactome)
CF IArrowREACT_460 (Reactome)
CF IIArrowREACT_45 (Reactome)
CF IIArrowREACT_460 (Reactome)
CF IIREACT_1724 (Reactome)
CF IREACT_1724 (Reactome)
CPSF

capped intronless pre-mRNA

CBC complex		REACT_336 (Reactome)
CPSFREACT_1652 (Reactome)
Capped Intronless Histone pre-mRNA CBC complexREACT_1591 (Reactome)
Capped Intronless Histone pre-mRNA CBC complexREACT_706 (Reactome)
Capped Intronless Histone pre-mRNA

CBP80 CBP20

SLBP		REACT_967 (Reactome)
CstF

CPSF capped intronless pre-mRNA

CBC complex		REACT_1724 (Reactome)
CstFArrowREACT_45 (Reactome)
CstFArrowREACT_460 (Reactome)
CstFREACT_336 (Reactome)
Mature Intronless transcript derived Histone mRNA

SLBP CBP80

CBP20		ArrowREACT_888 (Reactome)
Mature intronless derived mRNA complexArrowREACT_45 (Reactome)
Mature intronless transcript derived Histone pre-mRNA CBC complexArrowREACT_1222 (Reactome)
PABPN1ArrowREACT_45 (Reactome)
PABPN1REACT_1724 (Reactome)
PAPOLAArrowREACT_45 (Reactome)
PAPOLAREACT_1724 (Reactome)
REACT_1222 (Reactome) Processing is initiated once the U7 snRNP is loaded onto the pre-mRNA. The pre-mRNA HDE makes base-pairing contacts with the 5′ end of U7 snRNA. Binding of the U7 snRNP to the pre-mRNA is stabilized by interactions between a U7 snRNP protein, hZFP100 and other trans-acting factors, including the factor that catalyzes the cleavage reaction, which have yet to be defined. The cleavage occurs in the presence of EDTA as does the cleavage reaction in polyadenylation, it is likely that this reaction is catalyzed by a protein. There may well be additional proteins associated with the U7 snRNP, since the in vitro processing occurs in the absence of SLBP, it is possible that all the other factors required for processing are associated with the active form of the U7 snRNP.
REACT_1591 (Reactome) The U7 snRNP. This particle contains the U7 snRNA, the smallest of the snRNAs which varies from 57-70 nts long depending on the species. The 5’ end of U7 snRNA binds to a sequence 3’ of the stemloop, termed the histone downstream element (HDE). There are a number of proteins found in the U7 snRNP. There are 7 Sm proteins, as are present in the spliceosomal snRNP. Five of these proteins are the same as ones found in the spliceosomal snRNPs and there are 2, Lsm10 and Lsm11 that are unique to U7 snRNP.
REACT_1652 (Reactome) Poly(A) polymerase has no specificity for any particular RNA sequence, as well as a very low affinity for the RNA. Under physiological conditions, the activity of poly(A) polymerase depends on two auxiliary factors, both of which bind to specific RNA sequences and recruit the poly(A) polymerase by a direct contact. One of these proteins is the heterotetrameric CPSF, which binds the AAUAAA sequence and is also essential for 3' cleavage.
REACT_1724 (Reactome) CF I, which appears to be composed of two subunits, one of several related larger polypeptides and a common smaller one, also binds RNA, but with unknown specificity. RNA recognition by these proteins is cooperative. Cleavage also requires CF II, composed of at least two subunits, and poly(A) polymerase, the enzyme synthesizing the poly(A) tail in the second step of the reaction.
REACT_336 (Reactome) Endonucleolytic cleavage separates the pre-mRNA into an upstream fragment destined to become the mature mRNA and a downstream fragment that is rapidly degraded. Polyadenylation and cleavage occur concurrently, with complexes co-assembling, cleavage depends on two signals in the RNA, a highly conserved hexanucleotide, AAUAAA, 10 to 30 nucleotides upstream of the cleavage site, and a poorly conserved GU- or U-rich downstream element. Additional sequences, often upstream of AAUAAA, can enhance the efficiency of the reaction. Cleavage occurs most often after a CA dinucleotide. A single gene can have more than one 3' processing site.

Cleavage is preceded by the assembly of a large processing complex, the composition of which is poorly defined. ATP, but not its hydrolysis, is required for assembly. Cleavage depends on a number of protein factor. CPSF, a heterotetramer, binds specifically to the AAUAAA sequence. The heterotrimer CstF binds the GU- or U-rich downstream element.

REACT_45 (Reactome) The nuclear poly(A) binding protein (PABPN1), which binds the growing poly(A) tails once it has reached a length of about ten nucleotides. Stimulation of poly(A) polymerase by both CPSF and PABPN1 is synergistic and results in processive elongation of the RNA (the polymerase adds AMP residues without dissociating from the RNA). The processive reaction is terminated when the tail has reached a length of about 250 nucleotides.
REACT_460 (Reactome) The polypeptide catalyzing the hydrolysis of the phosphodiester bond remains to be identified. Cleavage produces a 3'-OH on the upstream fragment and a 5'-phosphate on the downstream fragment. At some unknown point after cleavage, the downstream fragment, CstF, CF I and CF II are thought to be released, whereas CPSF and poly(A) polymerase remain to carry out polyadenylation.
REACT_706 (Reactome) The 32 kDa stem-loop binding protein (SLBP), also termed hairpin binding protein (HBP) is likely the first protein that binds to the histone pre-mRNA as it is being transcribed.
REACT_888 (Reactome) Processing is initiated once the SLBP (bound to the stem loop) and the U7 snRNP (bound to the HDE) are both loaded onto the pre-mRNA. The pre-mRNA HDE makes base-pairing contacts with the 5′ end of U7 snRNA. Binding of the U7 snRNP to the pre-mRNA is stabilized by interactions between a U7 snRNP protein, hZFP100 and SLBP. It should be noted that there must be other trans-acting factors, including the factor that catalyzes the cleavage reaction, which have yet to be defined. The cleavage occurs in the presence of EDTA as does the cleavage reaction in polyadenylation, it is likely that this reaction is catalyzed by a protein. There may well be additional proteins associated with the U7 snRNP, and since in some conditions in vitro processing occurs in the absence of SLBP, it is possible that all the other factors required for processing are associated with the active form of the U7 snRNP.
REACT_967 (Reactome) The U7 snRNP. This particle contains the U7 snRNA, the smallest of the snRNAs which varies from 57-70 nts long depending on the species. The 5’ end of U7 snRNA binds to a sequence 3’ of the stemloop, termed the histone downstream element (HDE). There are a number of proteins found in the U7 snRNP. There are 7 Sm proteins, as are present in the spliceosomal snRNP. Five of these proteins are the same as ones found in the spliceosomal snRNPs and there are 2, Lsm10 and Lsm11 that are unique to U7 snRNP. A third protein joins the U7 snRNP, ZFP100, a large zinc finger protein. ZFP100 interacts with SLBP bound to the histone pre-mRNA and with Lsm11 and likely plays a critical role in recruiting U7 snRNP to the histone pre-mRNA.
SLBPREACT_706 (Reactome)
U7 snRNP ZNF473ArrowREACT_1222 (Reactome)
U7 snRNP ZNF473ArrowREACT_888 (Reactome)
U7 snRNP ZNF473REACT_1591 (Reactome)
U7 snRNP ZNF473REACT_967 (Reactome)
capped intronless pre-mRNA CBC complexREACT_1652 (Reactome)
downstream intronless mRNA fragmentArrowREACT_460 (Reactome)
upstream mRNA fragment

CPSF PAP

PABPN1 complex		ArrowREACT_460 (Reactome)

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