{{cs1 config|name-list-style=vanc|display-authors=6}} '''Cleavage stimulatory factor''' or '''cleavage stimulation factor''' ('''CstF''' or '''CStF''') is a heterotrimeric protein involved in the cleavage of the 3' signaling region from a newly synthesized pre-messenger RNA (mRNA) molecule.<ref name=":0">{{Citation |title=MRNA 3' End Processing and Metabolism |chapter=Poly(A) tail dynamics: Measuring polyadenylation, deadenylation and poly(A) tail length |date=2021-01-01 |series=Methods in Enzymology |volume=655 |pages=265–290 |publisher=Academic Press |doi=10.1016/bs.mie.2021.04.005 |pmid=34183126 |pmc=9015694 |isbn=978-0-12-823573-7 |language=en-US| vauthors = Murphy MR, Doymaz A, Kleiman FE }}</ref> It recognizes U/GU‑rich elements (GREs) downstream of pre‑mRNA cleavage sites and promotes endonucleolytic cleavage and subsequent polyadenylation (poly(A)) of eukaryotic pre‑mRNAs.<ref name=":02">{{Cite journal |last1=Beyer |first1=Katrin |last2=Dandekar |first2=Thomas |last3=Keller |first3=Walter |date=1997-10-17 |title=RNA Ligands Selected by Cleavage Stimulation Factor Contain Distinct Sequence Motifs That Function as Downstream Elements in 3′-End Processing of Pre-mRNA * |journal=Journal of Biological Chemistry |language=English |volume=272 |issue=42 |pages=26769–26779 |doi=10.1074/jbc.272.42.26769 |doi-access=free |pmid=9334264 |issn=0021-9258}}</ref>
CstF is recruited by cleavage and polyadenylation specificity factor (CPSF) and assembles into a protein complex on the 3' end to promote the synthesis of a functional polyadenine tail (poly(A) tail), which results in a mature mRNA molecule ready to be exported from the cell nucleus to the cytosol for translation.<ref name=":02" />
CstF is made up of the proteins CSTF1, CSTF2 and CSTF3, totaling about 200 kDa.<ref name=":2">{{Cite journal |last1=Takagaki |first1=Y |last2=Manley |first2=JL |date=2000-03-01 |title=Complex protein interactions within the human polyadenylation machinery identify a novel component. |journal=Molecular and Cellular Biology |volume=20 |issue=5 |pages=1515–1525 |doi=10.1128/MCB.20.5.1515-1525.2000 |issn=0035-6433 |pmid=10669729 |pmc=85326 }}</ref> CSTF2 is the primary RNA-binding subunit that recognizes GREs downstream of the cleavage site.<ref name=":02" />
The amount of CstF in a cell is dependent on the phase of the cell cycle, increasing significantly during the transition from G0 phase to S phase in mouse fibroblast and human splenic B cells.<ref>{{Cite journal |last1=Martincic |first1=K. |last2=Campbell |first2=R. |last3=Edwalds-Gilbert |first3=G. |last4=Souan |first4=L. |last5=Lotze |first5=M. T. |last6=Milcarek |first6=C. |year=1998 |title=Increase in the 64-kDa subunit of the polyadenylation/cleavage stimulatory factor during the G0 to S phase transition |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=95 |issue=19 |pages=11095–11100 |bibcode=1998PNAS...9511095M |doi=10.1073/pnas.95.19.11095 |pmc=21601 |pmid=9736695 |doi-access=free}}</ref>
== Structure == CstF is made of three subunits that each perform different functions of the larger protein complex.<ref name=":0" /> The subunits interact with each other to stabilize the complex and increase poly(A) efficiency.<ref name=":2" />
CSTF1 (also referred to as CstF-50) is the smallest subunit of CstF weighing around 50 kDa.<ref name=":2" /> It interacts with CSTF3 to support complex assembly, though the full mechanism is unknown.<ref>{{Cite web |last=Bank |first=RCSB Protein Data |title=RCSB PDB - 6B3X: Crystal structure of CstF-50 in complex with CstF-77 |url=https://www.rcsb.org/structure/6B3X |access-date=2025-12-04 |website=www.rcsb.org |language=en-US}}</ref> Studies speculate that CSTF1 acts as a clamp at the CSTF2 binding site on CSTF3, reducing flexibility in the bond and creating more favorable RNA binding.<ref>{{Cite journal |last1=Yang |first1=Wen |last2=Hsu |first2=Peter L |last3=Yang |first3=Fan |last4=Song |first4=Jae-Eun |last5=Varani |first5=Gabriele |date=2018-01-25 |title=Reconstitution of the CstF complex unveils a regulatory role for CstF-50 in recognition of 3′-end processing signals |url=http://academic.oup.com/nar/article/46/2/493/4647674 |journal=Nucleic Acids Research |language=en |volume=46 |issue=2 |pages=493–503 |doi=10.1093/nar/gkx1177 |issn=0305-1048 |pmc=5778602 |pmid=29186539}}</ref> Additionally, its N-terminus mediates homodimerization.<ref>{{Cite journal |last1=Moreno-Morcillo |first1=María |last2=Minvielle-Sébastia |first2=Lionel |last3=Mackereth |first3=Cameron |last4=Fribourg |first4=Sébastien |date=2011-03-01 |title=Hexameric architecture of CstF supported by CstF-50 homodimerization domain structure |url=http://rnajournal.cshlp.org/content/17/3/412 |journal=RNA |language=en |volume=17 |issue=3 |pages=412–418 |doi=10.1261/rna.2481011 |issn=1355-8382 |pmid=21233223|doi-access=free |pmc=3039141 }}</ref>
The second-largest CstF subunit is CSTF2 (also referred to as CstF-64) weighing around 64 kDa.<ref name=":2" /> It is the primary RNA-binding subunit and contains an RNA recognition motif (RRM) that binds to GREs in pre-mRNA.<ref>{{Cite thesis |last=Masoumzadeh |first=Elahe |date=May 2021|title=Structure and dynamics of CstF-64 RNA recognition motif drive cleavage and polyadenylation |hdl=2346/88257 |url=https://hdl.handle.net/2346/88257}}</ref> This binding attaches the poly(A) tail to the 3' end of pre-mRNAs, resulting in mature RNA. CSTF2 also affects cell growth, with studies finding that a significant reduction of CSTF2 in B cells reduces m-RNA accumulation and causes apoptosis upon depletion.<ref>{{Cite journal |last1=Takagaki |first1=Yoshio |last2=Manley |first2=James L |date=1998-12-01 |title=Levels of Polyadenylation Factor CstF-64 Control IgM Heavy Chain mRNA Accumulation and Other Events Associated with B Cell Differentiation |url=https://www.sciencedirect.com/science/article/pii/S1097276500802919 |journal=Molecular Cell |volume=2 |issue=6 |pages=761–771 |doi=10.1016/S1097-2765(00)80291-9 |pmid=9885564 |issn=1097-2765}}</ref>
CSTF3 (also referred to as CstF-77) is the largest subunit of CstF weighing around 77 kDa.<ref name=":2" /> It holds the larger complex together and stabilizes interactions between CSTF2 and 3'-end factors such as symplekin.<ref>{{Cite journal |last1=Ruepp |first1=Marc-David |last2=Schweingruber |first2=Christoph |last3=Kleinschmidt |first3=Nicole |last4=Schümperli |first4=Daniel |date=2011-01-01 |title=Interactions of CstF-64, CstF-77, and symplekin: implications on localisation and function |journal=Molecular Biology of the Cell |volume=22 |issue=1 |pages=91–104 |doi=10.1091/mbc.E10-06-0543 |issn=1939-4586 |pmc=3016980 |pmid=21119002}}</ref> It also interacts with CPSF subunit CPSF160, which is partially responsible for poly(A) site specification and synthesis of the poly(A) tail.<ref>{{Cite journal |last1=Murthy |first1=K G |last2=Manley |first2=J L |date=1995-11-01 |title=The 160-kD subunit of human cleavage-polyadenylation specificity factor coordinates pre-mRNA 3'-end formation |journal=Genes & Development |volume=9 |issue=21 |pages=2672–2683 |doi=10.1101/gad.9.21.2672 |issn=1549-5477 |pmid=7590244|doi-access=free }}</ref>
== Clinical significance ==
=== Cancer === Some studies have identified CSTF2 as a potential target for cancer detection and progression.<ref name=":05">{{Cite journal |last1=Ding |first1=Jiaxiang |last2=Su |first2=Yue |last3=Liu |first3=Youru |last4=Xu |first4=Yuanyuan |last5=Yang |first5=Dashuai |last6=Wang |first6=Xuefeng |last7=Hao |first7=Shuli |last8=Zhou |first8=Huan |last9=Li |first9=Hongtao |date=2023-12-17 |title=The role of CSTF2 in cancer: from technology to clinical application |url=https://doi.org/10.1080/15384101.2023.2299624 |journal=Cell Cycle |volume=22 |issue=23–24 |pages=2622–2636 |doi=10.1080/15384101.2023.2299624 |issn=1538-4101 |pmid=38166492 |pmc=10936678 }}</ref><ref name=":1">{{Cite journal |last1=Feng |first1=Linfei |last2=Jing |first2=Fengyang |last3=Qin |first3=Xiaofeng |last4=Zhou |first4=Liming |last5=Ning |first5=Yujie |last6=Hou |first6=Jun |last7=Kong |first7=Weihao |last8=Zhu |first8=Youming |date=2022-03-18 |title=Cleavage Stimulation Factor Subunit 2: Function Across Cancers and Potential Target for Chemotherapeutic Drugs |journal=Frontiers in Pharmacology |language=English |volume=13 |article-number=852469 |doi=10.3389/fphar.2022.852469 |doi-access=free |pmid=35370655 |issn=1663-9812|pmc=8971630 }}</ref> Certain cancers, including prostate cancer, breast cancer and pancreatic cancer, have been associated with elevated CSTF2 expression, suggesting that it contributes to the pathological development and progression of cancer.<ref name=":05" /> CSTF2 has been suggested for use as a biomarker for early cancer diagnosis and potential target for future drugs.<ref name=":1" /> There are currently no clinical applications of CSTF2 or CstF.<ref name=":1" />
== References == {{Reflist}}
== Further reading == {{refbegin}} * {{cite book | vauthors = Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J | date = 2004 | title = Molecular Cell Biology | publisher = WH Freeman | location = New York, NY | edition = 5th }} {{refend}}
== External links == * {{MeshName|Cleavage+stimulation+factor}}
{{RNA-binding proteins}} {{Post transcriptional modification}}
Category:Protein complexes Category:Gene expression Category:RNA-binding proteins