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{{Redirect|CPSF|Comité Paralympique et Sportif Français|French Paralympic and Sports Committee}}
{{Redirect|CPSF|Comité Paralympique et Sportif Français|French Paralympic and Sports Committee}}


'''Cleavage and polyadenylation specificity factor''' ('''CPSF''') is involved in the [[Bond cleavage|cleavage]] of the [[3']] signaling region from a newly synthesized pre-[[messenger RNA]] (pre-mRNA) molecule in the process of [[transcription (genetics)|gene transcription]]. It is the first protein to bind to the signaling region near the cleavage site of the pre-mRNA, to which the [[polyadenylation|poly(A) tail]] will be added by [[polynucleotide adenylyltransferase]]. The 10-30 nucleotide upstream signaling region of the cleavage site, polyadenylation signal (PAS), has the canonical [[nucleotide]] sequence AAUAAA, which is highly conserved across the vast majority of pre-mRNAs. The AAUAAA region is usually defined by a cytosine/adenine (CA) dinucleotide, which is the preferred sequence, that is 5' to the site of the endonucleolytic cleavage.<ref name=":1">{{Cite journal |last=Shi |first=Yongsheng |last2=Manley |first2=James L. |date=2015-05-01 |title=The end of the message: multiple protein–RNA interactions define the mRNA polyadenylation site |url=http://genesdev.cshlp.org/content/29/9/889 |journal=Genes & Development |language=en |volume=29 |issue=9 |pages=889–897 |doi=10.1101/gad.261974.115 |issn=0890-9369 |pmid=25934501}}</ref> <ref name=":2">{{Cite journal |last=Schönemann |first=Lars |last2=Kühn |first2=Uwe |last3=Martin |first3=Georges |last4=Schäfer |first4=Peter |last5=Gruber |first5=Andreas R. |last6=Keller |first6=Walter |last7=Zavolan |first7=Mihaela |last8=Wahle |first8=Elmar |date=2014-11-01 |title=Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33 |url=http://genesdev.cshlp.org/content/28/21/2381 |journal=Genes & Development |language=en |volume=28 |issue=21 |pages=2381–2393 |doi=10.1101/gad.250985.114 |issn=0890-9369 |pmid=25301781}}</ref> A second downstream signaling region, located on the portion of the pre-mRNA that is cleaved before polyadenylation, consists of a GU-rich region required for efficient processing. This downstream fragment is degraded. The mature RNA are transported into the cytoplasm, where they are translated into proteins.<ref name=":0">{{Cite journal |last=Sun |first=Yadong |last2=Zhang |first2=Yixiao |last3=Hamilton |first3=Keith |last4=Manley |first4=James L. |last5=Shi |first5=Yongsheng |last6=Walz |first6=Thomas |last7=Tong |first7=Liang |date=2018-02-13 |title=Molecular basis for the recognition of the human AAUAAA polyadenylation signal |url=https://pnas.org/doi/full/10.1073/pnas.1718723115 |journal=Proceedings of the National Academy of Sciences |language=en |volume=115 |issue=7 |doi=10.1073/pnas.1718723115 |issn=0027-8424 |pmc=PMC5816196 |pmid=29208711}}</ref>
'''Cleavage and polyadenylation specificity factor''' ('''CPSF''') is involved in the [[Bond cleavage|cleavage]] of the [[3']] signaling region from a newly synthesized pre-[[messenger RNA]] (pre-mRNA) molecule in the process of [[transcription (genetics)|gene transcription]]. It is the first protein to bind to the signaling region near the cleavage site of the pre-mRNA, to which the [[polyadenylation|poly(A) tail]] will be added by [[polynucleotide adenylyltransferase]]. The 10-30 nucleotide upstream signaling region of the cleavage site, polyadenylation signal (PAS), has the canonical [[nucleotide]] sequence AAUAAA, which is highly conserved across the vast majority of pre-mRNAs. The AAUAAA region is usually defined by a cytosine/adenine (CA) dinucleotide, which is the preferred sequence, that is 5' to the site of the endonucleolytic cleavage.<ref name=":1">{{Cite journal |last1=Shi |first1=Yongsheng |last2=Manley |first2=James L. |date=2015-05-01 |title=The end of the message: multiple protein–RNA interactions define the mRNA polyadenylation site |url=http://genesdev.cshlp.org/content/29/9/889 |journal=Genes & Development |language=en |volume=29 |issue=9 |pages=889–897 |doi=10.1101/gad.261974.115 |issn=0890-9369 |pmid=25934501|pmc=4421977 }}</ref> <ref name=":2">{{Cite journal |last1=Schönemann |first1=Lars |last2=Kühn |first2=Uwe |last3=Martin |first3=Georges |last4=Schäfer |first4=Peter |last5=Gruber |first5=Andreas R. |last6=Keller |first6=Walter |last7=Zavolan |first7=Mihaela |last8=Wahle |first8=Elmar |date=2014-11-01 |title=Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33 |url=http://genesdev.cshlp.org/content/28/21/2381 |journal=Genes & Development |language=en |volume=28 |issue=21 |pages=2381–2393 |doi=10.1101/gad.250985.114 |issn=0890-9369 |pmid=25301781|pmc=4215183 }}</ref> A second downstream signaling region, located on the portion of the pre-mRNA that is cleaved before polyadenylation, consists of a GU-rich region required for efficient processing. This downstream fragment is degraded. The mature RNA are transported into the cytoplasm, where they are translated into proteins.<ref name=":0">{{Cite journal |last1=Sun |first1=Yadong |last2=Zhang |first2=Yixiao |last3=Hamilton |first3=Keith |last4=Manley |first4=James L. |last5=Shi |first5=Yongsheng |last6=Walz |first6=Thomas |last7=Tong |first7=Liang |date=2018-02-13 |title=Molecular basis for the recognition of the human AAUAAA polyadenylation signal |journal=Proceedings of the National Academy of Sciences |language=en |volume=115 |issue=7 |pages=E1419–E1428 |doi=10.1073/pnas.1718723115 |issn=0027-8424 |pmc=5816196 |pmid=29208711 |bibcode=2018PNAS..115E1419S |doi-access=free }}</ref>


==Protein Structure & Interactions==
==Protein Structure & Interactions==
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CPSF-160 (160 kDa) is the largest subunit of CPSF and directly binds to the AAUAAA polyadenylation signal.<ref name=murthy1995>{{cite journal|last1=Murthy|first1=Kanneganti G K|last2=Manley|first2=James L|title=The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3'-end formation|journal=Genes & Development|date=1 November 1995|volume=9|issue=21|pages=2672–2683|doi=10.1101/gad.9.21.2672|url=http://genesdev.cshlp.org/content/9/21/2672.abstract|access-date=17 December 2014|pmid=7590244|doi-access=free}}</ref> 160 kDa has three β-propeller domains and a C-terminal domain.
CPSF-160 (160 kDa) is the largest subunit of CPSF and directly binds to the AAUAAA polyadenylation signal.<ref name=murthy1995>{{cite journal|last1=Murthy|first1=Kanneganti G K|last2=Manley|first2=James L|title=The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3'-end formation|journal=Genes & Development|date=1 November 1995|volume=9|issue=21|pages=2672–2683|doi=10.1101/gad.9.21.2672|url=http://genesdev.cshlp.org/content/9/21/2672.abstract|access-date=17 December 2014|pmid=7590244|doi-access=free}}</ref> 160 kDa has three β-propeller domains and a C-terminal domain.


CPSF-30 (30 kDa) has five Cys-Cys-Cys-His (CCCH) zinc-finger motifs near the N terminus and a CCCH zinc knuckle at the C terminus. Two isoforms of CPSF-30 exist and can be found in CPSF complexes. The RNA binding activity of CPSF-30 is mediated by its zinc-fingers 2 and 3. WD repeat domain 33 (146 kDa) has a WD40 domain near the N terminus. The WD40 domain interacts with RNA. WDR33 and CPSF-30 recognize the polyadenylation signal (PAS) in pre-mRNA, which aids in defining the position of RNA cleavage. CPSF-30 recognizes the AU-rich hexamer region by a cooperative, metal-dependent binding mechanism.<ref name=":1" /> <ref name=":0" /> <ref>{{Cite journal |last=Casañal |first=Ana |last2=Kumar |first2=Ananthanarayanan |last3=Hill |first3=Chris H. |last4=Easter |first4=Ashley D. |last5=Emsley |first5=Paul |last6=Degliesposti |first6=Gianluca |last7=Gordiyenko |first7=Yuliya |last8=Santhanam |first8=Balaji |last9=Wolf |first9=Jana |last10=Wiederhold |first10=Katrin |last11=Dornan |first11=Gillian L. |last12=Skehel |first12=Mark |last13=Robinson |first13=Carol V. |last14=Passmore |first14=Lori A. |date=2017-11-24 |title=Architecture of eukaryotic mRNA 3′-end processing machinery |url=https://www.sciencemag.org/lookup/doi/10.1126/science.aao6535 |journal=Science |language=en |volume=358 |issue=6366 |pages=1056–1059 |doi=10.1126/science.aao6535 |issn=0036-8075 |pmc=PMC5788269 |pmid=29074584}}</ref> <ref>{{Cite journal |last=Shimberg |first=Geoffrey D. |last2=Michalek |first2=Jamie L. |last3=Oluyadi |first3=Abdulafeez A. |last4=Rodrigues |first4=Andria V. |last5=Zucconi |first5=Beth E. |last6=Neu |first6=Heather M. |last7=Ghosh |first7=Shanchari |last8=Sureschandra |first8=Kanisha |last9=Wilson |first9=Gerald M. |last10=Stemmler |first10=Timothy L. |last11=Michel |first11=Sarah L. J. |date=2016-04-26 |title=Cleavage and polyadenylation specificity factor 30: An RNA-binding zinc-finger protein with an unexpected 2Fe–2S cluster |url=https://pnas.org/doi/full/10.1073/pnas.1517620113 |journal=Proceedings of the National Academy of Sciences |language=en |volume=113 |issue=17 |pages=4700–4705 |doi=10.1073/pnas.1517620113 |issn=0027-8424 |pmc=PMC4855568 |pmid=27071088}}</ref>
CPSF-30 (30 kDa) has five Cys-Cys-Cys-His (CCCH) zinc-finger motifs near the N terminus and a CCCH zinc knuckle at the C terminus. Two isoforms of CPSF-30 exist and can be found in CPSF complexes. The RNA binding activity of CPSF-30 is mediated by its zinc-fingers 2 and 3. WD repeat domain 33 (146 kDa) has a WD40 domain near the N terminus. The WD40 domain interacts with RNA. WDR33 and CPSF-30 recognize the polyadenylation signal (PAS) in pre-mRNA, which aids in defining the position of RNA cleavage. CPSF-30 recognizes the AU-rich hexamer region by a cooperative, metal-dependent binding mechanism.<ref name=":1" /> <ref name=":0" /> <ref>{{Cite journal |last1=Casañal |first1=Ana |last2=Kumar |first2=Ananthanarayanan |last3=Hill |first3=Chris H. |last4=Easter |first4=Ashley D. |last5=Emsley |first5=Paul |last6=Degliesposti |first6=Gianluca |last7=Gordiyenko |first7=Yuliya |last8=Santhanam |first8=Balaji |last9=Wolf |first9=Jana |last10=Wiederhold |first10=Katrin |last11=Dornan |first11=Gillian L. |last12=Skehel |first12=Mark |last13=Robinson |first13=Carol V. |last14=Passmore |first14=Lori A. |date=2017-11-24 |title=Architecture of eukaryotic mRNA 3′-end processing machinery |journal=Science |language=en |volume=358 |issue=6366 |pages=1056–1059 |doi=10.1126/science.aao6535 |issn=0036-8075 |pmc=5788269 |pmid=29074584}}</ref> <ref>{{Cite journal |last1=Shimberg |first1=Geoffrey D. |last2=Michalek |first2=Jamie L. |last3=Oluyadi |first3=Abdulafeez A. |last4=Rodrigues |first4=Andria V. |last5=Zucconi |first5=Beth E. |last6=Neu |first6=Heather M. |last7=Ghosh |first7=Shanchari |last8=Sureschandra |first8=Kanisha |last9=Wilson |first9=Gerald M. |last10=Stemmler |first10=Timothy L. |last11=Michel |first11=Sarah L. J. |date=2016-04-26 |title=Cleavage and polyadenylation specificity factor 30: An RNA-binding zinc-finger protein with an unexpected 2Fe–2S cluster |journal=Proceedings of the National Academy of Sciences |language=en |volume=113 |issue=17 |pages=4700–4705 |doi=10.1073/pnas.1517620113 |issn=0027-8424 |pmc=4855568 |pmid=27071088 |bibcode=2016PNAS..113.4700S |doi-access=free }}</ref>


Although CPSF-160 is the largest subunit of CPSF, a study conducted by Lars Schönemann and others debate that WDR33 is responsible for recognizing the PAS and not CPSF-160 as previously believed. The study concluded that the reason that CPSF-160 was believed to be responsible for recognizing the PAS was due to the fact that the WDR33 subunit had not been discovered at the time of the claim.<ref name=":2" />
Although CPSF-160 is the largest subunit of CPSF, a study conducted by Lars Schönemann and others debate that WDR33 is responsible for recognizing the PAS and not CPSF-160 as previously believed. The study concluded that the reason that CPSF-160 was believed to be responsible for recognizing the PAS was due to the fact that the WDR33 subunit had not been discovered at the time of the claim.<ref name=":2" />


Fip1 binds to U-rich RNAs by its arginine-rich C-terminus. It binds to RNA sequences upstream of the AAUAAA hexamer region in vitro. Fip1 and CPSF-160 recruit poly(A) polymerase (PAP) to the 3' processing site.<ref name=":1" /> PAP is stimulated by Poly(A) binding protein nuclear one to add the poly(A) tail, a non-templated adenosine residues, at the cleavage site. <ref name=":3" /> <ref>{{Citation |last=Murphy |first=Michael Robert |title=Chapter Thirteen - Poly(A) tail dynamics: Measuring polyadenylation, deadenylation and poly(A) tail length |date=2021-01-01 |url=https://www.sciencedirect.com/science/article/pii/S0076687921001403 |work=Methods in Enzymology |volume=655 |pages=265–290 |editor-last=Tian |editor-first=Bin |access-date=2023-11-28 |series=mRNA 3' End Processing and Metabolism |publisher=Academic Press |last2=Doymaz |first2=Ahmet |last3=Kleiman |first3=Frida Esther}}</ref>
Fip1 binds to U-rich RNAs by its arginine-rich C-terminus. It binds to RNA sequences upstream of the AAUAAA hexamer region in vitro. Fip1 and CPSF-160 recruit poly(A) polymerase (PAP) to the 3' processing site.<ref name=":1" /> PAP is stimulated by Poly(A) binding protein nuclear one to add the poly(A) tail, a non-templated adenosine residues, at the cleavage site. <ref name=":3" /> <ref>{{Citation |last1=Murphy |first1=Michael Robert |title=Chapter Thirteen - Poly(A) tail dynamics: Measuring polyadenylation, deadenylation and poly(A) tail length |date=2021-01-01 |journal=Methods in Enzymology |volume=655 |pages=265–290 |editor-last=Tian |editor-first=Bin |series=mRNA 3' End Processing and Metabolism |publisher=Academic Press |last2=Doymaz |first2=Ahmet |last3=Kleiman |first3=Frida Esther|doi=10.1016/bs.mie.2021.04.005 |pmid=34183126 |pmc=9015694 }}</ref>


CPSF recruits proteins to the 3' region. Identified proteins that are coordinated by CPSF activity include: [[cleavage stimulatory factor]] and the two poorly understood [[cleavage factor]]s. The binding of the [[polynucleotide adenylyltransferase]] responsible for actually synthesizing the tail is a necessary prerequisite for cleavage, thus ensuring that cleavage and polyadenylation are tightly coupled processes.
CPSF recruits proteins to the 3' region. Identified proteins that are coordinated by CPSF activity include: [[cleavage stimulatory factor]] and the two poorly understood [[cleavage factor]]s. The binding of the [[polynucleotide adenylyltransferase]] responsible for actually synthesizing the tail is a necessary prerequisite for cleavage, thus ensuring that cleavage and polyadenylation are tightly coupled processes.
Line 26: Line 26:
Symplekin is a scaffolding protein that mediates the interaction between CPSF and CstF.<ref name=":2" />
Symplekin is a scaffolding protein that mediates the interaction between CPSF and CstF.<ref name=":2" />


In mammalian CPSF, both cleavage factor I (CFI) and cleavage and polyadenylation specificity factor (CPSF) are required for cleavage and polyadenylation whereas cleavage stimulation factor (CstF) is only essential for the cleavage step.<ref>{{Cite journal |last=Stumpf |first=Gabi |last2=Domdey |first2=Horst |date=1996 |title=Dependence of Yeast Pre-mRNA 3′-End Processing on CFT1: A Sequence Homolog of the Mammalian AAUAAA Binding Factor |url=https://www.jstor.org/stable/2892223 |journal=Science |volume=274 |issue=5292 |pages=1517–1520 |issn=0036-8075}}</ref>
In mammalian CPSF, both cleavage factor I (CFI) and cleavage and polyadenylation specificity factor (CPSF) are required for cleavage and polyadenylation whereas cleavage stimulation factor (CstF) is only essential for the cleavage step.<ref>{{Cite journal |last1=Stumpf |first1=Gabi |last2=Domdey |first2=Horst |date=1996 |title=Dependence of Yeast Pre-mRNA 3′-End Processing on CFT1: A Sequence Homolog of the Mammalian AAUAAA Binding Factor |url=https://www.jstor.org/stable/2892223 |journal=Science |volume=274 |issue=5292 |pages=1517–1520 |doi=10.1126/science.274.5292.1517 |jstor=2892223 |pmid=8929410 |bibcode=1996Sci...274.1517S |s2cid=34840144 |issn=0036-8075}}</ref>


Cleavage stimulation factor (CstF) has three subunits: CstF77, CstF50, and CstF64. CstF recognizes the PAS that is 20 nucleotides downstream the signaling region of the cleavage site, which is a GU-rich [[sequence motif]] followed by U-rich sequences. CstF contributes to the selection of the cleavage site, as well as alternative polyadenylation.<ref name=":1" /> <ref name=":0" />
Cleavage stimulation factor (CstF) has three subunits: CstF77, CstF50, and CstF64. CstF recognizes the PAS that is 20 nucleotides downstream the signaling region of the cleavage site, which is a GU-rich [[sequence motif]] followed by U-rich sequences. CstF contributes to the selection of the cleavage site, as well as alternative polyadenylation.<ref name=":1" /> <ref name=":0" />


== Alternative Polyadenylation (APA) ==
== Alternative Polyadenylation (APA) ==
Alternative polyadenylation (APA) is a regulatory mechanism that forms multiple 3' end on mRNA.<ref name=":3">{{Cite journal |last=Arora |first=Ankita |last2=Goering |first2=Raeann |last3=Lo |first3=Hei Yong G. |last4=Lo |first4=Joelle |last5=Moffatt |first5=Charlie |last6=Taliaferro |first6=J. Matthew |date=2022 |title=The Role of Alternative Polyadenylation in the Regulation of Subcellular RNA Localization |url=https://www.frontiersin.org/articles/10.3389/fgene.2021.818668 |journal=Frontiers in Genetics |volume=12 |doi=10.3389/fgene.2021.818668/full |issn=1664-8021}}</ref>
Alternative polyadenylation (APA) is a regulatory mechanism that forms multiple 3' end on mRNA.<ref name=":3">{{Cite journal |last1=Arora |first1=Ankita |last2=Goering |first2=Raeann |last3=Lo |first3=Hei Yong G. |last4=Lo |first4=Joelle |last5=Moffatt |first5=Charlie |last6=Taliaferro |first6=J. Matthew |date=2022 |title=The Role of Alternative Polyadenylation in the Regulation of Subcellular RNA Localization |journal=Frontiers in Genetics |volume=12 |doi=10.3389/fgene.2021.818668 |pmid=35096024 |pmc=8795681 |issn=1664-8021 |doi-access=free }}</ref>


APA isoforms from the same gene can encode different proteins and/or contain different 3' untranslated regions (UTRs). Deregulation of APA has been associated with a number of human diseases.<ref name=":1" />
APA isoforms from the same gene can encode different proteins and/or contain different 3' untranslated regions (UTRs). Deregulation of APA has been associated with a number of human diseases.<ref name=":1" />

Revision as of 02:59, 28 November 2023

"CPSF" redirects here. For Comité Paralympique et Sportif Français, see French Paralympic and Sports Committee.

Cleavage and polyadenylation specificity factor (CPSF) is involved in the cleavage of the 3' signaling region from a newly synthesized pre-messenger RNA (pre-mRNA) molecule in the process of gene transcription. It is the first protein to bind to the signaling region near the cleavage site of the pre-mRNA, to which the poly(A) tail will be added by polynucleotide adenylyltransferase. The 10-30 nucleotide upstream signaling region of the cleavage site, polyadenylation signal (PAS), has the canonical nucleotide sequence AAUAAA, which is highly conserved across the vast majority of pre-mRNAs. The AAUAAA region is usually defined by a cytosine/adenine (CA) dinucleotide, which is the preferred sequence, that is 5' to the site of the endonucleolytic cleavage.[1] [2] A second downstream signaling region, located on the portion of the pre-mRNA that is cleaved before polyadenylation, consists of a GU-rich region required for efficient processing. This downstream fragment is degraded. The mature RNA are transported into the cytoplasm, where they are translated into proteins.[3]

Protein Structure & Interactions

In mammals, CPSF is a protein complex, consisting of six subunits: CPSF-73, CPSF-100, CPSF-30, CPSF-160, WDRR33, and Fip1.

The subunits form two components: mammalian polyadenylation specificity factors (mPSF) and mammalian cleavage factor (mCF). The mPSF is made up of CPSF-160, WDR33, CPSF-30, and Fip1. It is necessary for PAS recognition and polyadenylation. The mCF is made up of CPSF-73, CPSF-100, and symplekin. It catalyzes the cleavage reaction by recognizing the histone mRNA 3' processing site.[1] [3]

CPSF-73 is a zinc-dependent hydrolase which cleaves the mRNA precursor between a CA dinucleotide just downstream the polyadenylation signal sequence AAUAAA.[4] [5]

CPSF-100 contributes to the endonuclease activity of CPSF-73.[2]

CPSF-160 (160 kDa) is the largest subunit of CPSF and directly binds to the AAUAAA polyadenylation signal.[6] 160 kDa has three β-propeller domains and a C-terminal domain.

CPSF-30 (30 kDa) has five Cys-Cys-Cys-His (CCCH) zinc-finger motifs near the N terminus and a CCCH zinc knuckle at the C terminus. Two isoforms of CPSF-30 exist and can be found in CPSF complexes. The RNA binding activity of CPSF-30 is mediated by its zinc-fingers 2 and 3. WD repeat domain 33 (146 kDa) has a WD40 domain near the N terminus. The WD40 domain interacts with RNA. WDR33 and CPSF-30 recognize the polyadenylation signal (PAS) in pre-mRNA, which aids in defining the position of RNA cleavage. CPSF-30 recognizes the AU-rich hexamer region by a cooperative, metal-dependent binding mechanism.[1] [3] [7] [8]

Although CPSF-160 is the largest subunit of CPSF, a study conducted by Lars Schönemann and others debate that WDR33 is responsible for recognizing the PAS and not CPSF-160 as previously believed. The study concluded that the reason that CPSF-160 was believed to be responsible for recognizing the PAS was due to the fact that the WDR33 subunit had not been discovered at the time of the claim.[2]

Fip1 binds to U-rich RNAs by its arginine-rich C-terminus. It binds to RNA sequences upstream of the AAUAAA hexamer region in vitro. Fip1 and CPSF-160 recruit poly(A) polymerase (PAP) to the 3' processing site.[1] PAP is stimulated by Poly(A) binding protein nuclear one to add the poly(A) tail, a non-templated adenosine residues, at the cleavage site. [5] [9]

CPSF recruits proteins to the 3' region. Identified proteins that are coordinated by CPSF activity include: cleavage stimulatory factor and the two poorly understood cleavage factors. The binding of the polynucleotide adenylyltransferase responsible for actually synthesizing the tail is a necessary prerequisite for cleavage, thus ensuring that cleavage and polyadenylation are tightly coupled processes.

Other protein interaction

Symplekin is a scaffolding protein that mediates the interaction between CPSF and CstF.[2]

In mammalian CPSF, both cleavage factor I (CFI) and cleavage and polyadenylation specificity factor (CPSF) are required for cleavage and polyadenylation whereas cleavage stimulation factor (CstF) is only essential for the cleavage step.[10]

Cleavage stimulation factor (CstF) has three subunits: CstF77, CstF50, and CstF64. CstF recognizes the PAS that is 20 nucleotides downstream the signaling region of the cleavage site, which is a GU-rich sequence motif followed by U-rich sequences. CstF contributes to the selection of the cleavage site, as well as alternative polyadenylation.[1] [3]

Alternative Polyadenylation (APA)

Alternative polyadenylation (APA) is a regulatory mechanism that forms multiple 3' end on mRNA.[5]

APA isoforms from the same gene can encode different proteins and/or contain different 3' untranslated regions (UTRs). Deregulation of APA has been associated with a number of human diseases.[1]

Genes

References

  1. ^ a b c d e f Shi, Yongsheng; Manley, James L. (2015-05-01). "The end of the message: multiple protein–RNA interactions define the mRNA polyadenylation site". Genes & Development. 29 (9): 889–897. doi:10.1101/gad.261974.115. ISSN 0890-9369. PMC 4421977. PMID 25934501.
  2. ^ a b c d Schönemann, Lars; Kühn, Uwe; Martin, Georges; Schäfer, Peter; Gruber, Andreas R.; Keller, Walter; Zavolan, Mihaela; Wahle, Elmar (2014-11-01). "Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33". Genes & Development. 28 (21): 2381–2393. doi:10.1101/gad.250985.114. ISSN 0890-9369. PMC 4215183. PMID 25301781.
  3. ^ a b c d Sun, Yadong; Zhang, Yixiao; Hamilton, Keith; Manley, James L.; Shi, Yongsheng; Walz, Thomas; Tong, Liang (2018-02-13). "Molecular basis for the recognition of the human AAUAAA polyadenylation signal". Proceedings of the National Academy of Sciences. 115 (7): E1419–E1428. Bibcode:2018PNAS..115E1419S. doi:10.1073/pnas.1718723115. ISSN 0027-8424. PMC 5816196. PMID 29208711.
  4. ^ Mandel, Corey R.; Kaneko, Syuzo; Zhang, Hailong; Gebauer, Damara; Vethantham, Vasupradha; Manley, James L.; Tong, Liang (26 November 2006). "Polyadenylation factor CPSF-73 is the pre-mRNA 3'-end-processing endonuclease". Nature. 444 (7121): 953–956. Bibcode:2006Natur.444..953M. doi:10.1038/nature05363. PMC 3866582. PMID 17128255.
  5. ^ a b c Arora, Ankita; Goering, Raeann; Lo, Hei Yong G.; Lo, Joelle; Moffatt, Charlie; Taliaferro, J. Matthew (2022). "The Role of Alternative Polyadenylation in the Regulation of Subcellular RNA Localization". Frontiers in Genetics. 12. doi:10.3389/fgene.2021.818668. ISSN 1664-8021. PMC 8795681. PMID 35096024.
  6. ^ Murthy, Kanneganti G K; Manley, James L (1 November 1995). "The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3'-end formation". Genes & Development. 9 (21): 2672–2683. doi:10.1101/gad.9.21.2672. PMID 7590244. Retrieved 17 December 2014.
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