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Cleavage stimulation factor

From Wikipedia, the free encyclopedia

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.[1] 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.[2]

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.[2]

CstF is made up of the proteins CSTF1, CSTF2 and CSTF3, totaling about 200 kDa.[3] CSTF2 is the primary RNA-binding subunit that recognizes GREs downstream of the cleavage site.[2]

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.[4]

Structure

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CstF is made of three subunits that each perform different functions of the larger protein complex.[1] The subunits interact with each other to stabilize the complex and increase poly(A) efficiency.[3]

CSTF1 (also referred to as CstF-50) is the smallest subunit of CstF weighing around 50 kDa.[3] It interacts with CSTF3 to support complex assembly, though the full mechanism is unknown.[5] 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.[6] Additionally, its N-terminus mediates homodimerization.[7]

The second-largest CstF subunit is CSTF2 (also referred to as CstF-64) weighing around 64 kDa.[3] It is the primary RNA-binding subunit and contains an RNA recognition motif (RRM) that binds to GREs in pre-mRNA.[8] 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.[9]

CSTF3 (also referred to as CstF-77) is the largest subunit of CstF weighing around 77 kDa.[3] It holds the larger complex together and stabilizes interactions between CSTF2 and 3'-end factors such as symplekin.[10] It also interacts with CPSF subunit CPSF160, which is partially responsible for poly(A) site specification and synthesis of the poly(A) tail.[11]

Clinical significance

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Cancer

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Some studies have identified CSTF2 as a potential target for cancer detection and progression.[12][13] 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.[12] CSTF2 has been suggested for use as a biomarker for early cancer diagnosis and potential target for future drugs.[13] There are currently no clinical applications of CSTF2 or CstF.[13]

References

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  1. ^ a b "Poly(A) tail dynamics: Measuring polyadenylation, deadenylation and poly(A) tail length", Methods in Enzymology, vol. 655, Academic Press, pp. 265–290, 2021-01-01, retrieved 2025-12-04
  2. ^ a b c Beyer K, Dandekar T, Keller W (1997-10-17). "RNA Ligands Selected by Cleavage Stimulation Factor Contain Distinct Sequence Motifs That Function as Downstream Elements in 3′-End Processing of Pre-mRNA *". Journal of Biological Chemistry. 272 (42): 26769–26779. doi:10.1074/jbc.272.42.26769. ISSN 0021-9258.
  3. ^ a b c d e Takagaki Y, Manley JL (2000-03-01). "Complex protein interactions within the human polyadenylation machinery identify a novel component". Molecular and Cellular Biology. 20 (5): 1515–1525. ISSN 0035-6433. PMID 10669729.
  4. ^ Martincic K, Campbell R, Edwalds-Gilbert G, Souan L, Lotze MT, Milcarek C (1998). "Increase in the 64-kDa subunit of the polyadenylation/cleavage stimulatory factor during the G0 to S phase transition". Proceedings of the National Academy of Sciences of the United States of America. 95 (19): 11095–11100. Bibcode:1998PNAS...9511095M. doi:10.1073/pnas.95.19.11095. PMC 21601. PMID 9736695.
  5. ^ Bank RP. "RCSB PDB - 6B3X: Crystal structure of CstF-50 in complex with CstF-77". www.rcsb.org. Retrieved 2025-12-04.
  6. ^ Yang W, Hsu PL, Yang F, Song JE, Varani G (2018-01-25). "Reconstitution of the CstF complex unveils a regulatory role for CstF-50 in recognition of 3′-end processing signals". Nucleic Acids Research. 46 (2): 493–503. doi:10.1093/nar/gkx1177. ISSN 0305-1048. PMC 5778602. PMID 29186539.
  7. ^ Moreno-Morcillo M, Minvielle-Sébastia L, Mackereth C, Fribourg S (2011-03-01). "Hexameric architecture of CstF supported by CstF-50 homodimerization domain structure". RNA. 17 (3): 412–418. doi:10.1261/rna.2481011. ISSN 1355-8382. PMID 21233223.
  8. ^ Masoumzadeh E (May 2021). Structure and dynamics of CstF-64 RNA recognition motif drive cleavage and polyadenylation (Thesis).
  9. ^ Takagaki Y, Manley JL (1998-12-01). "Levels of Polyadenylation Factor CstF-64 Control IgM Heavy Chain mRNA Accumulation and Other Events Associated with B Cell Differentiation". Molecular Cell. 2 (6): 761–771. doi:10.1016/S1097-2765(00)80291-9. ISSN 1097-2765.
  10. ^ Ruepp MD, Schweingruber C, Kleinschmidt N, Schümperli D (2011-01-01). "Interactions of CstF-64, CstF-77, and symplekin: implications on localisation and function". Molecular Biology of the Cell. 22 (1): 91–104. doi:10.1091/mbc.E10-06-0543. ISSN 1939-4586. PMC 3016980. PMID 21119002.
  11. ^ Murthy KG, Manley JL (1995-11-01). "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. ISSN 1549-5477. PMID 7590244.
  12. ^ a b Ding J, Su Y, Liu Y, Xu Y, Yang D, Wang X, et al. (2023-12-17). "The role of CSTF2 in cancer: from technology to clinical application". Cell Cycle. 22 (23–24): 2622–2636. doi:10.1080/15384101.2023.2299624. ISSN 1538-4101. PMID 38166492.
  13. ^ a b c Feng L, Jing F, Qin X, Zhou L, Ning Y, Hou J, et al. (2022-03-18). "Cleavage Stimulation Factor Subunit 2: Function Across Cancers and Potential Target for Chemotherapeutic Drugs". Frontiers in Pharmacology. 13. doi:10.3389/fphar.2022.852469. ISSN 1663-9812.

Further reading

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  • Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, et al. (2004). Molecular Cell Biology (5th ed.). New York, NY: WH Freeman.
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