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.Any covalent change in a primary (nascent) mRNA transcript is mRNA Processing. For successful gene expression, the primary mRNA transcript needs to be converted to a mature mRNA prior to its translation into polypeptide. Eucaryotic mRNAs undergo a series of complex processing reactions; these begin on nascent transcripts as soon as a few ribonucleotides have been synthesized during transcription by RNA Polymerase II, through the export of the mature mRNA to the cytoplasm, and culminate with mRNA turnover in the cytoplasm.
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The U1 snRNP is a particle consisting of the U1 snRNA and Sm core plus unique snRNP polypeptides. The U1-specific polypeptides are 70K, A, and C. The Sm core polypeptides are B, B', D1, D2, D3, E, F, G. The Sm core is a heteroheptamer in the shape of a donut, containing either B or B', which are almost identical to each other.
Histone mRNAs are exported by a mechanism that requires TAP, the key factor requires for transport of polyadenylated mRNAs. How TAP is recruited to the histone mRNAs is not known, but it is clear that transport can occur in the absence of either the stemloop or of SLBP. The mature transcript docks at the NPC, in the course of transport CBC will be lost from the mRNA cap, and remain in the nucleous.
At the beginning of this reaction, 1 molecule of 'Magoh-Y14 complex', and 1 molecule of 'Spliceosomal active C complex with lariat containing, 5'-end cleaved pre-mRNP:CBC complex' are present. At the end of this reaction, 1 molecule of 'Exon Junction Complex' is present.
The cytoplasmic 3' polyadenylated, capped intronless mRNA and TAP are released from the NPC into the cytosol. Cytosolic TAP will be recycled to the nucleous, while the 3' polyadenylated, capped intronless mRNA is bound by eIF4E and destined for translation.
Once the transport complex is fully assembled the mature mRNA can be translocated from the nucleoplasm to the cytoplasm. The assembled complex starts at the nucleoplasmic basket, travels through the pore, and ends it journey at the cytoplasmic face of the nuclear pore complex.
The mRNA is transferred from ALYREF of the TREX complex to NXF1 (TAP) of the NXF1:NXT1 export complex (Hautbergue et al. 2008). Interaction between the TREX complex and NXF1 exposes the arginine-rich RNA-binding domain of NXF1 (Viphakone et al. 2012). Methylation of arginine residues on ALYREF also appears to be necessary for dissociation of mRNA from ALYREF during the transfer (Hung et al. 2010). The interaction between ALYREF and NXF1 occurs in the vicinity of nuclear speckles (Teng and Wilson 2013). DDX39B (UAP56) binds (Kota et al. 2008) and hydrolyzes ATP (Taniguchi and Ohno 2008). UAP56 is believed to hydrolyze ATP and UAP56:ADP is believed to dissociate at some point during the transfer of the mRNA to NXF1 (Taniguchi and Ohno 2008, Chang et al. 2013).
In addition to the methylation of the 5'-cap, there is methylation of internal nucleotides in the mRNA. This methylation can occur in translated and untranslated regions. One to three methyl groups have been seen per mRNA molecule, but methylation is non-stoichiometric. The most frequent methylation observed is at the N6 position of adenosine. The function of mRNA internal methylation, if any, is unknown.
After the nascent pre-mRNA undergoes the initial capping and methylation reactions, it gets associated with numerous factors, including the various heterogeneous nuclear ribonucleoproteins (hnRNPS), the nuclear Cap-Binding Complex, and many splicing factors that make the pre-mRNA a substrate for splicing, 3'-end processing, and in some cases editing.
Pre-mRNA transcripts become rapidly associated with many RNA-binding proteins, including hnRNP proteins, cap-binding proteins, SR proteins, etc; in the test tube this binding does not require splice sites or ATP. The E complex, or early complex, is the first detectable functional intermediate in spliceosome assembly in vitro. It is an ATP-independent complex. When a functional 5' splice site is present, it is bound by the U1 snRNP. The splicing factor U2AF (65 and 35 kDa subunits) binds to the polypyrimidine tract (Y)n and the AG dinucleotide at the 3' splice site, respectively. SF1/mBBP binds to the branch site. Binding of many of these factors is cooperative; e.g., SR proteins and U2AF apparently interact with each other, facilitating their binding to the pre-mRNA. In the presence of ATP, the E complex is converted to the first ATP-dependent spliceosomal complex, namely the A complex.
The A complex is the first ATP-dependent complex in spliceosome assembly. U2AF recruits the U2 snRNP to bind to the branch site in the E complex in an ATP-dependent fashion, to form the A complex. The U2 snRNA base-pairs with the branch site, causing the branch-site adenosine to bulge out, which later positions it for nucleophilic attack at the 5' splice site. The A complex serves as a substrate for formation of the B complex.
The formation of the B complex is ATP-dependent, and both the 5' and 3' splice sites are essential for B complex assembly. The U4 and U6 snRNPS are extensively base-paired, and this U4:U6 complex associates with the U5 snRNP to form a tri-snRNP particle. This tri-snRNP particle then binds to the spliceosomal A complex, to form the spliceosomal B complex.
The intermediate spliceosomal C complex (also called the Bact or B(act) complex) is a very short-lived intermediate; the splicing intermediates are rapidly converted to splicing products. Also, the spliced products are released very rapidly, and no complex containing both the splicing products has been isolated. Conversion of the spliceosomal B complex to the spliceosomal C complex requires ATP. The extensive base-pairing between the U4 and U6 snRNAs is disrupted during the formation of the C complex, which is thought to require helicase-type activity associated with the DEAD box factors. The U4 snRNP and U1 snRNP dissociate from the complex and the LSM2-6 complex of the U6 snRNP is lost, apparently allowing the U6 snRNA to then base-pair with the U2 snRNA and the 5' end of the splice site on the mRNA (Bessonov et al. 2010).
The active C complex is formed due to a conformational change in the intermediate C complex. After formation of the active C complex, the splicing reactions occur very rapidly.
In the first catalytic step of mRNA splicing, the 2' OH group of the bulged A at the branch site performs a nucleophilic attack on the 5' splice site phosphodiester bond, resulting in cleavage of the bond between the 5' exon and the 5' end of the intron, and formation of a new bond between the 5' end of the intron and the branch site A. This results in a lariat-shaped intermediate, with the intron still attached to the 3' exon. The branch site A has a 2'-5' phosphodiester bond with the G at the beginning of the intron, in addition to the usual 5'-3' and 3'-5'phosphodiester bonds.
The second step of the splicing reaction results in cleavage of the transcript at the 3'splice site, and results in ligation of the two exons and excision of the intron.
Endonucleolytic cleavage separates the pre-mRNA into an upstream fragment destined to become the mature mRNA, and a downstream fragment that is rapidly degraded. 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 at the 3'-end of mRNAs depends on a number of protein factors. CPSF, a heterotetramer, binds specifically to the AAUAAA sequence. The heterotrimer CstF binds the downstream element. 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. 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 RNA fragment, CstF, CF I and CF II are thought to be released, whereas CPSF and poly(A) polymerase remain to carry out polyadenylation.
The upstream fragment generated by 3' cleavage of the pre-mRNA receives a poly(A) tail of approximately 250 AMP residues in a reaction depending on the AAUAAA sequence 10 to 30 nucleotides upstream of the 3' end. Polyadenylation is carried out by three proteins: Poly(A) polymerase carries the catalytic activity. The enzyme has no specificity for any particular RNA sequence, and it also has a very low affinity for the RNA.
Under physiological conditions, the activity of poly(A) polymerase thus depends on two auxiliary factors, both of which bind to specific RNA sequences and recruit the enzyme by a direct contact. One of these proteins is the heterotetrameric CPSF, which binds the AAUAAA sequence and is also essential for 3' cleavage. The second is the nuclear poly(A) binding protein (PABPN1), which binds the growing poly(A) tails once this has reached a length of about ten nucleotides. Stimulation of poly(A) polymerase by both proteins is synergistic and results in processive elongation of the RNA, i.e. 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.
At the beginning of this reaction, 1 molecule of 'ATAC B Complex' is present. At the end of this reaction, 1 molecule of 'U4 ATAC snRNP', and 1 molecule of 'ATAC C Complex' are present.
U12-type AT-AC introns are distinguished from the major U2-type introns by the consensus sequences of their highly conserved splicing signals. U12 introns have the 5' ss consensus sequence (G/A)TATCCTTT, the branchpoint sequence TTTCCTTAACT and the 3' ss (C/T)AG. Initial recognition of AT-AC introns involves interaction of U12 snRNP with the branch-point sequence and U11 with the 5' ss. Unlike the major splicing pathway, U11 and U12 are in a complex and interact with the pre-mRNA simultaneously, binding in an ATP-dependent manner as a di-snRNP complex and likely bridging the 5' ss and 3' ss region.
Twenty proteins have been identified in the U11/U12 di-snRNP complex including the snRNP Sm proteins B’, B, D3, D2, D1, E, F, and G which are identical to the major splicing pathway Sm proteins. A U2 snRNP core protein complex, SF3b is also found in the U11/U12 di-snRNP, including p14, a protein that interacts with the branchpoint adenosine.
SR proteins are required for formation of A complex in AT-AC splicing. The same SR proteins involved in splicing of the major introns are also active in splicing of AT-AC introns, though, as in the major pathway, there is substrate specificity.
The U4atac/U6atac enters the spliceosome and U6atac snRNA forms base pairing interactions with the 5' ss and also forms base pairing interactions with U12 and U4atac is partially displaced. U5 snRNP, the only snRNP common to both the major and minor splicing pathways, also joins the spliceosome to form the B complex and interacts with nucleotides within the 3' end of the exon flanking the 5' ss.
At the beginning of this reaction, 1 molecule of 'ATAC C Complex' is present. At the end of this reaction, 1 molecule of 'ATAC C Complex with lariat containing 5'-end cleaved mRNA' is present.
At the beginning of this reaction, 1 molecule of 'ATAC C Complex with lariat containing 5'-end cleaved mRNA' is present. At the end of this reaction, 1 molecule of 'U6 ATAC snRNP', 1 molecule of 'post exon ligation complex', 1 molecule of 'U12 snRNP', 1 molecule of 'U11 snRNP', and 1 molecule of 'U5 snRNP' are present.
At the beginning of this reaction, 1 molecule of 'TAP:3'-polyadenylated, capped mRNA complex' is present. At the end of this reaction, 1 molecule of 'SRp55', 1 molecule of 'U2AF 65 kDa subunit', 1 molecule of 'SR9 / SRp30', 1 molecule of 'hTra2', 1 molecule of 'hPrp16', 1 molecule of 'SR 11/ p54', 1 molecule of 'hPrp22', 1 molecule of 'SRp40', 1 molecule of 'hPrp17', 1 molecule of 'SF2/ASF/SFRS1', 1 molecule of 'hSLU7', 1 molecule of 'Export Receptor bound mature mRNA Complex', 1 molecule of 'U2AF 35 kDa subunit', 1 molecule of 'SR2 / SC35', 1 molecule of 'hPrp43', 1 molecule of 'SRp20', 1 molecule of 'SR7/ 9G8 protein', 1 molecule of 'hPrp18', and 1 molecule of 'SR4 / SRp75' are present.
At the beginning of this reaction, 1 molecule of and 1 molecule of 'Export Receptor bound mature mRNA Complex' are present. At the end of this reaction, 1 molecule of 'THOC4(Aly/Ref)', 1 molecule of 'Mature mRNP Complex', 1 molecule of 'SRm160', and 1 molecule of 'TAP' are present.
Histone mRNAs are exported by a mechanism that requires TAP, the key factor requires for transport of polyadenylated mRNAs. How TAP is recruited to the histone mRNAs is not known, but it is clear that transport can occur in the absence of either the stemloop or of SLBP. The stemloop and SLBP enhance the rate of transport of histone mRNAs in Xenopus oocytes, but are not essential for transport
The polyadenylated, capped transcript and TAP dock at the nucleoplasmic side of the NPC. The Cap Binding Complex (CBC) and CPSF complexes are released back into the nucleoplasm.
The THO subcomplex of the TREX complex initially interacts with the serine-2,5 phosphorylated C-terminal domain of RNA polymerase II (Strasser et al. 2002, Inferred from yeast in Meinel et al. 2013) then with CBP80 of the cap binding complex (Cheng et al. 2006, Dufu et al. 2010, Chi et al. 2013). A TREX complex binds spliced mRNA near the cap during transcription (Cheng et al. 2006). Recruitment is dependent on splicing of the mRNA (Masuda et al. 2005). THO/TREX is required for efficient mRNP biogenesis and export (reviewed in Luna et al 2012). In yeast, components of the THO/TREX complex also affect transcription and 3' processing of mRNA, (Rondon et al. 2003, Rougemaille et al. 2008, Johnson et al. 2011, reviewed in Katahira 2015), however the human TREX complex does not appear to affect transcription (Masuda et al. 2005). The AREX complex, which contains DDX39A (UHR49) rather than DDX39B (UAP56) appears to perform the same function as TREX in mRNA export, but acts on a different subset of mRNAs (Yamazaki et al. 2010).
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DataNodes
ligated exon
containing complexlariat containing
5'-end cleaved mRNAPolyadenylation
ComplexIntronless transcript derived Histone
mRNA:SLBP:CBP80:CBP20intronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexintronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexTranscript Derived Histone mRNA:TAP:Aly/Ref
ComplexTranscript Derived Histone mRNA:TAP:Aly/Ref
complexTranscript Derived
mRNA:eIF4E Complexindependent Histone
mRNA:eIF4E complexderived mRNA:TAP:Aly/Ref
complexderived mRNA
complextranscript derived Histone mRNA:SLBP:eIF4E
Complextranscript derived Histone pre-mRNA:CBC
complexintronless derived mRNA:TAP:Aly/Ref
complexpolymerase II
(phosphorylated):TFIIF complexIntermediate C
(Bact) ComplexC complex with lariat containing, 5'-end cleaved pre-mRNP:CBC
complexpre-mRNA:CBC:RNA Pol II (phosphorylated)
complexpre-mRNA:CBC
Complexpre-mRNP:CBC
complexcapped
mRNA:CBC:EJC:TREX:SRSF proteinsAnnotated Interactions
ligated exon
containing complexligated exon
containing complexlariat containing
5'-end cleaved mRNAlariat containing
5'-end cleaved mRNAPolyadenylation
ComplexPolyadenylation
ComplexIntronless transcript derived Histone
mRNA:SLBP:CBP80:CBP20intronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexintronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexintronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexintronless transcript derived Histone
mRNA:SLBP:TAP:Aly/Ref complexTranscript Derived Histone mRNA:TAP:Aly/Ref
ComplexTranscript Derived Histone mRNA:TAP:Aly/Ref
ComplexTranscript Derived Histone mRNA:TAP:Aly/Ref
complexTranscript Derived Histone mRNA:TAP:Aly/Ref
complexTranscript Derived
mRNA:eIF4E Complexindependent Histone
mRNA:eIF4E complexderived mRNA:TAP:Aly/Ref
complexderived mRNA:TAP:Aly/Ref
complexderived mRNA
complextranscript derived Histone mRNA:SLBP:eIF4E
Complextranscript derived Histone pre-mRNA:CBC
complexintronless derived mRNA:TAP:Aly/Ref
complexintronless derived mRNA:TAP:Aly/Ref
complexThis reaction takes place in the 'nucleoplasm'.
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 at the 3'-end of mRNAs depends on a number of protein factors. CPSF, a heterotetramer, binds specifically to the AAUAAA sequence. The heterotrimer CstF binds the downstream element. 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. 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 RNA fragment, CstF, CF I and CF II are thought to be released, whereas CPSF and poly(A) polymerase remain to carry out polyadenylation.
Under physiological conditions, the activity of poly(A) polymerase thus depends on two auxiliary factors, both of which bind to specific RNA sequences and recruit the enzyme by a direct contact. One of these proteins is the heterotetrameric CPSF, which binds the AAUAAA sequence and is also essential for 3' cleavage. The second is the nuclear poly(A) binding protein (PABPN1), which binds the growing poly(A) tails once this has reached a length of about ten nucleotides. Stimulation of poly(A) polymerase by both proteins is synergistic and results in processive elongation of the RNA, i.e. 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.
This reaction takes place in the 'nucleus'.
Twenty proteins have been identified in the U11/U12 di-snRNP complex including the snRNP Sm proteins B’, B, D3, D2, D1, E, F, and G which are identical to the major splicing pathway Sm proteins. A U2 snRNP core protein complex, SF3b is also found in the U11/U12 di-snRNP, including p14, a protein that interacts with the branchpoint adenosine.
SR proteins are required for formation of A complex in AT-AC splicing. The same SR proteins involved in splicing of the major introns are also active in splicing of AT-AC introns, though, as in the major pathway, there is substrate specificity.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleus'.
This reaction takes place in the 'nucleoplasm'.
This reaction takes place in the 'nuclear envelope'.
This reaction takes place in the 'cytoplasm'.
polymerase II
(phosphorylated):TFIIF complexIntermediate C
(Bact) ComplexIntermediate C
(Bact) ComplexIntermediate C
(Bact) ComplexC complex with lariat containing, 5'-end cleaved pre-mRNP:CBC
complexC complex with lariat containing, 5'-end cleaved pre-mRNP:CBC
complexpre-mRNA:CBC:RNA Pol II (phosphorylated)
complexpre-mRNA:CBC
Complexpre-mRNA:CBC
Complexpre-mRNA:CBC
Complexpre-mRNP:CBC
complexpre-mRNP:CBC
complexcapped
mRNA:CBC:EJC:TREX:SRSF proteinscapped
mRNA:CBC:EJC:TREX:SRSF proteinscapped
mRNA:CBC:EJC:TREX:SRSF proteins