Processing of Capped Intronless Pre-mRNA (Homo sapiens)

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Bibliography

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

External references

DataNodes

Name	Type	Database reference	Comment
ATP	Metabolite	CHEBI:15422 (ChEBI)
CF I - 68 kDa subunit		R-HSA-72013 (Reactome)
CF I - 72 kDa subunit		R-HSA-72014 (Reactome)
CF II	Complex	R-HSA-72020 (Reactome)
CF I	Complex	R-HSA-72015 (Reactome)
CLP1	Protein	Q92989 (Uniprot-TrEMBL)
CPSF1	Protein	Q10570 (Uniprot-TrEMBL)
CPSF2	Protein	Q9P2I0 (Uniprot-TrEMBL)
CPSF3	Protein	Q9UKF6 (Uniprot-TrEMBL)
CPSF4	Protein	O95639 (Uniprot-TrEMBL)
CPSF7	Protein	Q8N684 (Uniprot-TrEMBL)
CPSF:capped intronless pre-mRNA:CBC complex	Complex	R-HSA-112160 (Reactome)
CPSF	Complex	R-HSA-71995 (Reactome)
CSTF1	Protein	Q05048 (Uniprot-TrEMBL)
CSTF2	Protein	P33240 (Uniprot-TrEMBL)
CSTF2T	Protein	Q9H0L4 (Uniprot-TrEMBL)
CSTF3	Protein	Q12996 (Uniprot-TrEMBL)
Capped Intronless Histone pre-mRNA:CBP80:CBP20:SLBP:ZFP100 Complex	Complex	R-HSA-110766 (Reactome)
Capped Intronless Histone pre-mRNA:CBP80:CBP20:SLBP	Complex	R-HSA-110759 (Reactome)
Capped Intronless Histone pre-mRNA:CBC complex	Complex	R-HSA-110758 (Reactome)
Capped Intronless Histone pre-mRNA:CBC:ZFP100 Complex	Complex	R-HSA-112045 (Reactome)
Capped intronless pre-mRNA		R-NUL-112158 (Reactome)
CstF:CPSF:capped intronless pre-mRNA:CBC complex	Complex	R-HSA-112161 (Reactome)
CstF	Complex	R-HSA-72006 (Reactome)
FIP1L1	Protein	Q6UN15 (Uniprot-TrEMBL)
Intronless Histone pre-mRNA		R-NUL-110756 (Reactome)
LSM10	Protein	Q969L4 (Uniprot-TrEMBL)
LSM11	Protein	P83369 (Uniprot-TrEMBL)
Mature Intronless transcript derived Histone mRNA:SLBP:CBP80:CBP20	Complex	R-HSA-111682 (Reactome)
Mature Intronless transcript derived Histone mRNA		R-NUL-111676 (Reactome)
Mature intronless derived mRNA complex	Complex	R-HSA-112167 (Reactome)
Mature intronless transcript derived Histone pre-mRNA:CBC complex	Complex	R-HSA-156959 (Reactome)
Mature intronless transcript derived mRNA		R-NUL-158444 (Reactome)	A mature mRNA that has been 3' cleaved, subsequently polyadenylated, and a m7G 5' cap. This product was derived from an intronless transcript.
NCBP1	Protein	Q09161 (Uniprot-TrEMBL)
NCBP2	Protein	P52298 (Uniprot-TrEMBL)
NUDT21	Protein	O43809 (Uniprot-TrEMBL)
PABPN1	Protein	Q86U42 (Uniprot-TrEMBL)
PABPN1	Protein	Q86U42 (Uniprot-TrEMBL)
PAPOLA	Protein	P51003 (Uniprot-TrEMBL)
PAPOLA	Protein	P51003 (Uniprot-TrEMBL)
PCF11	Protein	O94913 (Uniprot-TrEMBL)
SLBP	Protein	Q14493 (Uniprot-TrEMBL)
SLBP	Protein	Q14493 (Uniprot-TrEMBL)
SNRPB	Protein	P14678 (Uniprot-TrEMBL)
SNRPD3	Protein	P62318 (Uniprot-TrEMBL)
SNRPE	Protein	P62304 (Uniprot-TrEMBL)
SNRPF	Protein	P62306 (Uniprot-TrEMBL)
SNRPG	Protein	P62308 (Uniprot-TrEMBL)
SYMPK	Protein	Q92797 (Uniprot-TrEMBL)
U7 snRNA		R-NUL-110761 (Reactome)
U7 snRNP:ZNF473	Complex	R-HSA-110765 (Reactome)
WDR33	Protein	Q9C0J8 (Uniprot-TrEMBL)
ZNF473	Protein	Q8WTR7 (Uniprot-TrEMBL)
capped intronless pre-mRNA:CBC complex	Complex	R-HSA-112159 (Reactome)
downstream intronless mRNA fragment		R-NUL-112165 (Reactome)
intronless pre-mRNA cleavage complex	Complex	R-HSA-112162 (Reactome)
upstream mRNA fragment:CPSF:PAP:PABPN1 complex	Complex	R-HSA-112164 (Reactome)
upstream intronless mRNA fragment		R-NUL-112163 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
ATP			R-HSA-77591 (Reactome)
	CF I	Arrow	R-HSA-77592 (Reactome)
	CF I	Arrow	R-HSA-77593 (Reactome)
	CF II	Arrow	R-HSA-77592 (Reactome)
	CF II	Arrow	R-HSA-77593 (Reactome)
CF II			R-HSA-77591 (Reactome)
CF I			R-HSA-77591 (Reactome)
	CPSF:capped intronless pre-mRNA:CBC complex	Arrow	R-HSA-77589 (Reactome)
CPSF:capped intronless pre-mRNA:CBC complex			R-HSA-77590 (Reactome)
CPSF			R-HSA-77589 (Reactome)
	Capped Intronless Histone pre-mRNA:CBP80:CBP20:SLBP:ZFP100 Complex	Arrow	R-HSA-77585 (Reactome)
Capped Intronless Histone pre-mRNA:CBP80:CBP20:SLBP:ZFP100 Complex			R-HSA-77586 (Reactome)
	Capped Intronless Histone pre-mRNA:CBP80:CBP20:SLBP	Arrow	R-HSA-77584 (Reactome)
Capped Intronless Histone pre-mRNA:CBP80:CBP20:SLBP			R-HSA-77585 (Reactome)
Capped Intronless Histone pre-mRNA:CBC complex			R-HSA-111438 (Reactome)
Capped Intronless Histone pre-mRNA:CBC complex			R-HSA-77584 (Reactome)
	Capped Intronless Histone pre-mRNA:CBC:ZFP100 Complex	Arrow	R-HSA-111438 (Reactome)
Capped Intronless Histone pre-mRNA:CBC:ZFP100 Complex			R-HSA-111437 (Reactome)
	CstF:CPSF:capped intronless pre-mRNA:CBC complex	Arrow	R-HSA-77590 (Reactome)
CstF:CPSF:capped intronless pre-mRNA:CBC complex			R-HSA-77591 (Reactome)
	CstF	Arrow	R-HSA-77592 (Reactome)
	CstF	Arrow	R-HSA-77593 (Reactome)
CstF			R-HSA-77590 (Reactome)
	Mature Intronless transcript derived Histone mRNA:SLBP:CBP80:CBP20	Arrow	R-HSA-77586 (Reactome)
	Mature intronless derived mRNA complex	Arrow	R-HSA-77593 (Reactome)
	Mature intronless transcript derived Histone pre-mRNA:CBC complex	Arrow	R-HSA-111437 (Reactome)
	PABPN1	Arrow	R-HSA-77593 (Reactome)
PABPN1			R-HSA-77591 (Reactome)
	PAPOLA	Arrow	R-HSA-77593 (Reactome)
PAPOLA			R-HSA-77591 (Reactome)
			R-HSA-111437 (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�² 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.
			R-HSA-111438 (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.
			R-HSA-77584 (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.
			R-HSA-77585 (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.
			R-HSA-77586 (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�² 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.
			R-HSA-77589 (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.
			R-HSA-77590 (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.
			R-HSA-77591 (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.
			R-HSA-77592 (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.
			R-HSA-77593 (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.
SLBP			R-HSA-77584 (Reactome)
	U7 snRNP:ZNF473	Arrow	R-HSA-111437 (Reactome)
	U7 snRNP:ZNF473	Arrow	R-HSA-77586 (Reactome)
U7 snRNP:ZNF473			R-HSA-111438 (Reactome)
U7 snRNP:ZNF473			R-HSA-77585 (Reactome)
capped intronless pre-mRNA:CBC complex			R-HSA-77589 (Reactome)
	downstream intronless mRNA fragment	Arrow	R-HSA-77592 (Reactome)
	intronless pre-mRNA cleavage complex	Arrow	R-HSA-77591 (Reactome)
intronless pre-mRNA cleavage complex			R-HSA-77592 (Reactome)
intronless pre-mRNA cleavage complex			R-HSA-77593 (Reactome)
	upstream mRNA fragment:CPSF:PAP:PABPN1 complex	Arrow	R-HSA-77592 (Reactome)