cleavage stimulation factor


Summary: A RNA-binding protein that stimulates the cleavage of the 3' end of MRNA near the POLYADENYLATION site. It is a heterotrimer of 55-, 64- and 77-kDa subunits and combines with CLEAVAGE STIMULATION FACTOR to form a stable complex with mRNA that directs the 3' cleavage and polyadenylation reaction.

Top Publications

  1. Ruepp M, Schweingruber C, Kleinschmidt N, Schumperli D. Interactions of CstF-64, CstF-77, and symplekin: implications on localisation and function. Mol Biol Cell. 2011;22:91-104 pubmed publisher
    ..Thus, the interactions between CstF-64/CstF-64Tau and CstF-77 are important for the maintenance of stoichiometric nuclear levels of the CstF complex components and for their intracellular localization, stability, and function. ..
  2. Mirkin N, Fonseca D, Mohammed S, Cevher M, Manley J, Kleiman F. The 3' processing factor CstF functions in the DNA repair response. Nucleic Acids Res. 2008;36:1792-804 pubmed publisher
    ..Our results indicate that CstF plays an active role in the response to DNA damage, providing a link between transcription-coupled RNA processing and DNA repair. ..
  3. Monarez R, MacDonald C, Dass B. Polyadenylation proteins CstF-64 and tauCstF-64 exhibit differential binding affinities for RNA polymers. Biochem J. 2007;401:651-8 pubmed
    CstF-64 (cleavage stimulation factor-64), a major regulatory protein of polyadenylation, is absent during male meiosis. Therefore a paralogous variant, tauCstF-64 is expressed in male germ cells to maintain normal spermatogenesis...
  4. Martincic K, Alkan S, Cheatle A, Borghesi L, Milcarek C. Transcription elongation factor ELL2 directs immunoglobulin secretion in plasma cells by stimulating altered RNA processing. Nat Immunol. 2009;10:1102-9 pubmed publisher
    ..Thus, loading of ELL2 and CstF-64 on RNA polymerase II was linked, caused enhanced use of the proximal poly(A) site and was necessary for processing of immunoglobulin heavy-chain mRNA. ..
  5. Huber Z, Monarez R, Dass B, MacDonald C. The mRNA encoding tauCstF-64 is expressed ubiquitously in mouse tissues. Ann N Y Acad Sci. 2005;1061:163-72 pubmed
    ..These results suggest the hypothesis that tauCstF-64 mRNA is regulated at the translational or post-translational level. ..
  6. Bai Y, Auperin T, Chou C, Chang G, Manley J, Tong L. Crystal structure of murine CstF-77: dimeric association and implications for polyadenylation of mRNA precursors. Mol Cell. 2007;25:863-75 pubmed
    b>Cleavage stimulation factor (CstF) is a heterotrimeric protein complex essential for polyadenylation of mRNA precursors...
  7. Legrand P, Pinaud N, Minvielle Sebastia L, Fribourg S. The structure of the CstF-77 homodimer provides insights into CstF assembly. Nucleic Acids Res. 2007;35:4515-22 pubmed
    The cleavage stimulation factor (CstF) is essential for the first step of poly(A) tail formation at the 3' ends of mRNAs. This heterotrimeric complex is built around the 77-kDa protein bridging both CstF-64 and CstF-50 subunits...
  8. Maciolek N, McNally M. Characterization of Rous sarcoma virus polyadenylation site use in vitro. Virology. 2008;374:468-76 pubmed publisher
  9. Takagaki Y, Manley J. A polyadenylation factor subunit is the human homologue of the Drosophila suppressor of forked protein. Nature. 1994;372:471-4 pubmed
    ..b>Cleavage stimulation factor (CstF) is one of these, functioning together with cleavage-polyadenylation specificity factor, two ..

More Information


  1. Rozenblatt Rosen O, Nagaike T, FRANCIS J, Kaneko S, Glatt K, Hughes C, et al. The tumor suppressor Cdc73 functionally associates with CPSF and CstF 3' mRNA processing factors. Proc Natl Acad Sci U S A. 2009;106:755-60 pubmed publisher
    ..that Cdc73 physically associates with the cleavage and polyadenylation specificity factor (CPSF) and cleavage stimulation factor (CstF) complexes that are required for the maturation of mRNA 3' ends in the cell nucleus...
  2. Pan Z, Zhang H, Hague L, Lee J, Lutz C, Tian B. An intronic polyadenylation site in human and mouse CstF-77 genes suggests an evolutionarily conserved regulatory mechanism. Gene. 2006;366:325-34 pubmed
    Human CstF-77 is one of the three subunits of cleavage stimulation factor (CstF) that is essential for mRNA polyadenylation...
  3. Kolev N, Steitz J. Symplekin and multiple other polyadenylation factors participate in 3'-end maturation of histone mRNAs. Genes Dev. 2005;19:2583-92 pubmed
    ..all five subunits of the cleavage and polyadenylation specificity factor (CPSF), two subunits of the cleavage stimulation factor (CstF), and symplekin...
  4. Shell S, Hesse C, Morris S, Milcarek C. Elevated levels of the 64-kDa cleavage stimulatory factor (CstF-64) in lipopolysaccharide-stimulated macrophages influence gene expression and induce alternative poly(A) site selection. J Biol Chem. 2005;280:39950-61 pubmed
  5. Malatesta M, Perdoni F, Muller S, Zancanaro C, Pellicciari C. Nuclei of aged myofibres undergo structural and functional changes suggesting impairment in RNA processing. Eur J Histochem. 2009;53:97-106 pubmed
    ..This failure likely contributes to the reduced responsiveness of muscle cells to anabolic stimuli in the elderly. ..
  6. Phillips C, Pachikara N, Gunderson S. U1A inhibits cleavage at the immunoglobulin M heavy-chain secretory poly(A) site by binding between the two downstream GU-rich regions. Mol Cell Biol. 2004;24:6162-71 pubmed
    ..We demonstrate here that U1A binds two (AUGCN(1-3)C) motifs within the 29-nucleotide sequence and inhibits the binding of cleavage stimulatory factor 64K and cleavage at the secretory poly(A) site. ..
  7. Wallace A, Denison T, Attaya E, MacDonald C. Developmental distribution of the polyadenylation protein CstF-64 and the variant tauCstF-64 in mouse and rat testis. Biol Reprod. 2004;70:1080-7 pubmed
    ..Second, unlike in mice, tauCstF-64 was expressed at significant levels in rat liver. These differences in expression suggest interesting differences in X-chromosomal gene expression between these two rodent species. ..
  8. Hockert J, Yeh H, MacDonald C. The hinge domain of the cleavage stimulation factor protein CstF-64 is essential for CstF-77 interaction, nuclear localization, and polyadenylation. J Biol Chem. 2010;285:695-704 pubmed publisher
    ..Further, we showed that the Hinge domain is necessary for CstF-64 interaction with CstF-77 and consequent nuclear localization, suggesting that nuclear import of a preformed CstF complex is an essential step in polyadenylation. ..
  9. Salisbury J, Hutchison K, Graber J. A multispecies comparison of the metazoan 3'-processing downstream elements and the CstF-64 RNA recognition motif. BMC Genomics. 2006;7:55 pubmed
    The Cleavage Stimulation Factor (CstF) is a required protein complex for eukaryotic mRNA 3'-processing...
  10. Qu X, Perez Canadillas J, Agrawal S, De Baecke J, Cheng H, Varani G, et al. The C-terminal domains of vertebrate CstF-64 and its yeast orthologue Rna15 form a new structure critical for mRNA 3'-end processing. J Biol Chem. 2007;282:2101-15 pubmed
    ..These results define the role of the C-terminal half of Rna15 and provide insight into the network of protein/protein interactions responsible for assembly of the 3 '-end processing apparatus. ..
  11. Dass B, Tardif S, Park J, Tian B, Weitlauf H, Hess R, et al. Loss of polyadenylation protein tauCstF-64 causes spermatogenic defects and male infertility. Proc Natl Acad Sci U S A. 2007;104:20374-9 pubmed
    ..CstF-64, the RNA-binding component of the cleavage stimulation factor (CstF), interacts with pre-mRNAs at sequences downstream of the cleavage site...
  12. Tardif S, Akrofi A, Dass B, Hardy D, MacDonald C. Infertility with impaired zona pellucida adhesion of spermatozoa from mice lacking TauCstF-64. Biol Reprod. 2010;83:464-72 pubmed publisher
    ..To our knowledge, this is the first demonstration that a gene involved in polyadenylation has a negative consequence on sperm-ZP adhesion. ..
  13. Yang W, Hsu P, Yang F, Song J, Varani G. Reconstitution of the CstF complex unveils a regulatory role for CstF-50 in recognition of 3'-end processing signals. Nucleic Acids Res. 2017;: pubmed publisher
    b>Cleavage stimulation factor (CstF) is a highly conserved protein complex composed of three subunits that recognizes G/U-rich sequences downstream of the polyadenylation signal of eukaryotic mRNAs...
  14. Harris J, Martinez J, Grozdanov P, Bergeson S, Grammas P, MacDonald C. The Cstf2t Polyadenylation Gene Plays a Sex-Specific Role in Learning Behaviors in Mice. PLoS ONE. 2016;11:e0165976 pubmed publisher
    ..CstF-64 (the 64,000 Mr subunit of the cleavage stimulation factor; gene symbol Cstf2) is an RNA-binding protein that regulates mRNA polyadenylation site usage...
  15. Fonseca D, Baquero J, Murphy M, Aruggoda G, Varriano S, Sapienza C, et al. mRNA Processing Factor CstF-50 and Ubiquitin Escort Factor p97 Are BRCA1/BARD1 Cofactors Involved in Chromatin Remodeling during the DNA Damage Response. Mol Cell Biol. 2018;38: pubmed publisher
    ..In this study, we provide evidence of the roles of the polyadenylation factor cleavage stimulation factor 50 (CstF-50) and the ubiquitin (Ub) escort factor p97 as cofactors of BRCA1/BARD1 E3 Ub ligase, ..
  16. Akman H, Oyken M, Tuncer T, Can T, Erson Bensan A. 3'UTR shortening and EGF signaling: implications for breast cancer. Hum Mol Genet. 2015;24:6910-20 pubmed publisher
    ..To begin addressing the underlying mechanisms, we found CSTF2 (cleavage stimulation factor 2), a major regulator of 3'UTR shortening to be up-regulated in response to epidermal growth factor (..
  17. Tan S, Ding K, Chong Q, Zhao J, Liu Y, Shao Y, et al. Post-transcriptional regulation of ERBB2 by miR26a/b and HuR confers resistance to tamoxifen in estrogen receptor-positive breast cancer cells. J Biol Chem. 2017;292:13551-13564 pubmed publisher
    ..of the HuR mRNA 3'-UTR via alternative polyadenylation (APA) was observed to be dependent on cleavage stimulation factor subunit 2 (CSTF2/CstF-64), which is up-regulated in the TAMR breast cancer cells...
  18. Shankarling G, MacDonald C. Polyadenylation site-specific differences in the activity of the neuronal ?CstF-64 protein in PC-12 cells. Gene. 2013;529:220-7 pubmed publisher
    ..Our data address the polyadenylation functions of ?CstF-64 for the first time, and provide initial insights into the mechanism of alternative poly(A) site selection in the nervous system. ..
  19. McCracken S, Longman D, Johnstone I, Caceres J, Blencowe B. An evolutionarily conserved role for SRm160 in 3'-end processing that functions independently of exon junction complex formation. J Biol Chem. 2003;278:44153-60 pubmed
    ..Simultaneous RNAi of SRm160 and the cleavage factor CstF-50 (Cleavage stimulation factor 50-kDa subunit) resulted in late embryonic developmental arrest...
  20. Li W, Yeh H, Shankarling G, Ji Z, Tian B, MacDonald C. The ?CstF-64 polyadenylation protein controls genome expression in testis. PLoS ONE. 2012;7:e48373 pubmed publisher
    ..These results suggest that ?CstF-64 plays a role in 3' end determination and transcription termination for a large range of germ cell-expressed genes...
  21. Rouget C, Papin C, Mandart E. Cytoplasmic CstF-77 protein belongs to a masking complex with cytoplasmic polyadenylation element-binding protein in Xenopus oocytes. J Biol Chem. 2006;281:28687-98 pubmed
    ..However, the kinetic of Mos mRNA polyadenylation is not modified. Furthermore, X77K represses mRNA translation in vitro. These results suggest that X77K could be involved in masking of mRNA prior to polyadenylation. ..
  22. Bai Y, Auperin T, Tong L. The use of in situ proteolysis in the crystallization of murine CstF-77. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2007;63:135-8 pubmed
    ..After an extensive search, it was found that 55% glucose can be used as a cryoprotectant while maintaining the diffraction quality of the crystals; most other commonly used cryoprotectants were detrimental to the diffraction quality. ..
  23. Addepalli B, Hunt A. The interaction between two Arabidopsis polyadenylation factor subunits involves an evolutionarily-conserved motif and has implications for the assembly and function of the polyadenylation complex. Protein Pept Lett. 2008;15:76-88 pubmed
    ..Taken together, these results suggest that Fip1 is situated near CstF64 in the polyadenylation complex. ..
  24. Sunden Y, Semba S, Suzuki T, Okada Y, Orba Y, Nagashima K, et al. Identification of DDX1 as a JC virus transcriptional control region-binding protein. Microbiol Immunol. 2007;51:327-37 pubmed
    ..Using column chromatographic purifi-cation and microsequencing, we identified cleavage stimulation factor (CstF) as a component of #3-bp...
  25. Nag A, Narsinh K, Martinson H. The poly(A)-dependent transcriptional pause is mediated by CPSF acting on the body of the polymerase. Nat Struct Mol Biol. 2007;14:662-9 pubmed
    ..Pausing does not require the RNA polymerase II C-terminal domain (CTD) or the cleavage stimulation factor, CstF, that binds the CTD...
  26. Shandilya J, Wang Y, Roberts S. TFIIB dephosphorylation links transcription inhibition with the p53-dependent DNA damage response. Proc Natl Acad Sci U S A. 2012;109:18797-802 pubmed publisher required to drive the formation of gene promoter-3' processing site contacts through the cleavage stimulation factor 3' (CstF 3')-processing complex...
  27. Davidson L, West S. Splicing-coupled 3' end formation requires a terminal splice acceptor site, but not intron excision. Nucleic Acids Res. 2013;41:7101-14 pubmed publisher
    ..These data suggest that early stages of spliceosome assembly are sufficient to functionally couple splicing and 3' end formation, but that on-going intron removal is less critical. ..
  28. Avendaño Vázquez S, Dhir A, Bembich S, Buratti E, Proudfoot N, Baralle F. Autoregulation of TDP-43 mRNA levels involves interplay between transcription, splicing, and alternative polyA site selection. Genes Dev. 2012;26:1679-84 pubmed publisher
    ..Overall, we uncover complex interplay between transcription, splicing, and 3' end processing to effect autoregulation of TDP-43. ..
  29. Shi M, Zhang H, Wu X, He Z, Wang L, Yin S, et al. ALYREF mainly binds to the 5' and the 3' regions of the mRNA in vivo. Nucleic Acids Res. 2017;45:9640-9653 pubmed publisher
  30. Malatesta M, Perdoni F, Muller S, Pellicciari C, Zancanaro C. Pre-mRNA processing is partially impaired in satellite cell nuclei from aged muscles. J Biomed Biotechnol. 2010;2010:410405 pubmed publisher
    ..We demonstrated that in satellite cells the RNA pathways undergo alterations during aging, possibly hampering their responsiveness to muscle damage. ..
  31. Cui M, Allen M, Larsen A, MacMorris M, Han M, Blumenthal T. Genes involved in pre-mRNA 3'-end formation and transcription termination revealed by a lin-15 operon Muv suppressor screen. Proc Natl Acad Sci U S A. 2008;105:16665-70 pubmed publisher
    ..recognized by a protein complex that includes cleavage polyadenylation specificity factor (CPSF) and cleavage stimulation factor (CstF)...
  32. Sunden Y, Semba S, Suzuki T, Okada Y, Orba Y, Nagashima K, et al. DDX1 promotes proliferation of the JC virus through transactivation of its promoter. Microbiol Immunol. 2007;51:339-47 pubmed
    Recently, we demonstrated that the DEAD box protein 1 (DDX1), an RNA helicase, and the cleavage stimulation factor (CstF) form a complex that binds to the JC virus transcriptional control region (JCV-TCR)...
  33. Yao Y, Song L, Katz Y, Galili G. Cloning and characterization of Arabidopsis homologues of the animal CstF complex that regulates 3' mRNA cleavage and polyadenylation. J Exp Bot. 2002;53:2277-8 pubmed
    ..These results imply that these Arabidopsis homologues belong to the polyadenylation machinery of nuclear mRNAs. ..
  34. Proudfoot N, O Sullivan J. Polyadenylation: a tail of two complexes. Curr Biol. 2002;12:R855-7 pubmed
    ..These connections improve the efficiency of polyadenylation and signal to the polymerase to terminate transcription; their discovery reveals another level of gene regulation. ..
  35. Gawande B, Robida M, Rahn A, Singh R. Drosophila Sex-lethal protein mediates polyadenylation switching in the female germline. EMBO J. 2006;25:1263-72 pubmed
    ..The sex-specific poly(A) switching of e(r) provides a means for translational regulation in germ cells. We present a model for the SXL-dependent poly(A) site choice in the female germline. ..
  36. Herr A, Molnar A, Jones A, Baulcombe D. Defective RNA processing enhances RNA silencing and influences flowering of Arabidopsis. Proc Natl Acad Sci U S A. 2006;103:14994-5001 pubmed
    ..According to this proposal, in the absence of these ESP proteins, these RNAs have aberrant 3' termini. The aberrant RNAs would enter the RNA silencing pathways because they are converted into dsRNA by RNA-dependent RNA polymerases. ..
  37. Shankarling G, Coates P, Dass B, MacDonald C. A family of splice variants of CstF-64 expressed in vertebrate nervous systems. BMC Mol Biol. 2009;10:22 pubmed publisher
    ..We propose that betaCstF-64 contributes to proteomic diversity by regulating alternative polyadenylation of neural mRNAs. ..
  38. Sullivan K, Steiniger M, Marzluff W. A core complex of CPSF73, CPSF100, and Symplekin may form two different cleavage factors for processing of poly(A) and histone mRNAs. Mol Cell. 2009;34:322-32 pubmed publisher
    ..These results suggest that a common core cleavage factor is required for processing of histone and polyadenylated pre-mRNAs. ..
  39. Liu F, Marquardt S, Lister C, Swiezewski S, Dean C. Targeted 3' processing of antisense transcripts triggers Arabidopsis FLC chromatin silencing. Science. 2010;327:94-7 pubmed publisher
    ..Targeted 3' processing of antisense transcripts may be a common mechanism triggering transcriptional silencing of the corresponding sense gene. ..
  40. Edwards R, Lee M, Tsutakawa S, Williams R, Nazeer I, Kleiman F, et al. The BARD1 C-terminal domain structure and interactions with polyadenylation factor CstF-50. Biochemistry. 2008;47:11446-56 pubmed publisher
    ..BARD1 architecture and plasticity imparted by the ANK-BRCT linker are suitable to allow the BARD1 C-terminus to act as a hub with multiple binding sites to integrate diverse DNA damage signals directly to RNA polymerase. ..
  41. Banwait S, Galvan V, Zhang J, Gorostiza O, Ataie M, Huang W, et al. C-terminal cleavage of the amyloid-beta protein precursor at Asp664: a switch associated with Alzheimer's disease. J Alzheimers Dis. 2008;13:1-16 pubmed
  42. Luo W, Ji Z, Pan Z, You B, Hoque M, Li W, et al. The conserved intronic cleavage and polyadenylation site of CstF-77 gene imparts control of 3' end processing activity through feedback autoregulation and by U1 snRNP. PLoS Genet. 2013;9:e1003613 pubmed publisher
    ..Thus, the conserved intronic pA of the CstF-77 gene may function as a sensor for cellular C/P and splicing activities, controlling the homeostasis of CstF-77 and C/P activity and impacting cell proliferation and differentiation. ..
  43. Bell S, Hunt A. The Arabidopsis ortholog of the 77 kDa subunit of the cleavage stimulatory factor (AtCstF-77) involved in mRNA polyadenylation is an RNA-binding protein. FEBS Lett. 2010;584:1449-54 pubmed publisher
    The 77 kDa subunit of the polyadenylation cleavage stimulation factor (CstF77) is important in messenger RNA 3' end processing...
  44. Xiang K, Tong L, Manley J. Delineating the structural blueprint of the pre-mRNA 3'-end processing machinery. Mol Cell Biol. 2014;34:1894-910 pubmed publisher
  45. Yang Q, Gilmartin G, DOUBLIE S. The structure of human cleavage factor I(m) hints at functions beyond UGUA-specific RNA binding: a role in alternative polyadenylation and a potential link to 5' capping and splicing. RNA Biol. 2011;8:748-53 pubmed publisher
    ..element and UGUA upstream element are recognized by the cleavage and polyadenylation factor (CPSF), cleavage stimulation factor (CstF) and cleavage factor I(m) (CFI(m)), respectively...
  46. Grozdanov P, Amatullah A, Graber J, MacDonald C. TauCstF-64 Mediates Correct mRNA Polyadenylation and Splicing of Activator and Repressor Isoforms of the Cyclic AMP-Responsive Element Modulator (CREM) in Mouse Testis. Biol Reprod. 2016;94:34 pubmed publisher
  47. Misra A, Green M. From polyadenylation to splicing: Dual role for mRNA 3' end formation factors. RNA Biol. 2016;13:259-64 pubmed publisher
    ..Our understanding of the roles of 3' end formation factors is still evolving, and the final picture might be more complex than originally envisioned. ..
  48. Nazeer F, Devany E, Mohammed S, Fonseca D, Akukwe B, Taveras C, et al. p53 inhibits mRNA 3' processing through its interaction with the CstF/BARD1 complex. Oncogene. 2011;30:3073-83 pubmed publisher
    ..Here, we identify a novel 3' RNA processing inhibitory function of p53, adding a new level of complexity to the DDR by linking RNA processing to the p53 network. ..
  49. López Camarillo C, Orozco E, Marchat L. Entamoeba histolytica: comparative genomics of the pre-mRNA 3' end processing machinery. Exp Parasitol. 2005;110:184-90 pubmed
    ..From these analyses, we propose a hypothetical working model for the pre-mRNA 3' end processing machinery in E. histolytica. ..
  50. Tsuzuki M, Wu W, Nishikawa H, Hayami R, Oyake D, Yabuki Y, et al. A truncated splice variant of human BARD1 that lacks the RING finger and ankyrin repeats. Cancer Lett. 2006;233:108-16 pubmed
    ..DeltaRIN does not interact with BRCA1, whereas it interacts with and colocalizes with CstF-50 to cytoplasmic dots. Hence, a deletion variant of BARD1 occurs in cells and may play a distinct role with CstF-50. ..
  51. Moreno Morcillo M, Minvielle Sebastia L, Mackereth C, Fribourg S. Hexameric architecture of CstF supported by CstF-50 homodimerization domain structure. RNA. 2011;17:412-8 pubmed publisher
    The Cleavage stimulation Factor (CstF) complex is composed of three subunits and is essential for pre-mRNA 3'-end processing...