1932

Abstract

Formation of the 3′ end of a eukaryotic mRNA is a key step in the production of a mature transcript. This process is mediated by a number of protein factors that cleave the pre-mRNA, add a poly(A) tail, and regulate transcription by protein dephosphorylation. Cleavage and polyadenylation specificity factor (CPSF) in humans, or cleavage and polyadenylation factor (CPF) in yeast, coordinates these enzymatic activities with each other, with RNA recognition, and with transcription. The site of pre-mRNA cleavage can strongly influence the translation, stability, and localization of the mRNA. Hence, cleavage site selection is highly regulated. The length of the poly(A) tail is also controlled to ensure that every transcript has a similar tail when it is exported from the nucleus. In this review, we summarize new mechanistic insights into mRNA 3′-end processing obtained through structural studies and biochemical reconstitution and outline outstanding questions in the field.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-biochem-052521-012445
2023-06-20
2024-10-06
Loading full text...

Full text loading...

/deliver/fulltext/biochem/92/1/annurev-biochem-052521-012445.html?itemId=/content/journals/10.1146/annurev-biochem-052521-012445&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Hocine S, Singer RH, Grünwald D. 2010. RNA processing and export. Cold Spring Harb. Perspect. Biol. 2:a000752
    [Google Scholar]
  2. 2.
    Tian B, Manley JL. 2016. Alternative polyadenylation of mRNA precursors. Nat. Rev. Mol. Cell Biol. 18:18–30
    [Google Scholar]
  3. 3.
    Gruber AJ, Zavolan M. 2019. Alternative cleavage and polyadenylation in health and disease. Nat. Rev. Genet. 20:599–614
    [Google Scholar]
  4. 4.
    Passmore LA, Coller J. 2021. Roles of mRNA poly(A) tails in regulation of eukaryotic gene expression. Nat. Rev. Mol. Cell Biol. 23:93–106
    [Google Scholar]
  5. 5.
    Buratowski S. 2005. Connections between mRNA 3′ end processing and transcription termination. Curr. Opin. Cell Biol. 17:257–61
    [Google Scholar]
  6. 6.
    Shi Y, Di Giammartino DC, Taylor D, Sarkeshik A, Rice WJ et al. 2009. Molecular architecture of the human pre-mRNA 3′ processing complex. Mol. Cell 33:365–76
    [Google Scholar]
  7. 7.
    Kumar A, Clerici M, Muckenfuss LM, Passmore LA, Jinek M. 2019. Mechanistic insights into mRNA 3′-end processing. Curr. Opin. Struct. Biol. 59:143–50
    [Google Scholar]
  8. 8.
    Zhang Y, Sun Y, Shi Y, Walz T, Tong L. 2020. Structural insights into the human pre-mRNA 3′-end processing machinery. Mol. Cell 77:800–9
    [Google Scholar]
  9. 9.
    Casañal A, Kumar A, Hill CH, Easter AD, Emsley P et al. 2017. Architecture of eukaryotic mRNA 3′-end processing machinery. Science 358:1056–59
    [Google Scholar]
  10. 10.
    Boreikaitė V, Elliott TS, Chin JW, Passmore LA. 2022. RBBP6 activates the pre-mRNA 3′ end processing machinery in humans. Genes Dev. 36:210–24
    [Google Scholar]
  11. 11.
    Schmidt M, Kluge F, Sandmeir F, Schäfer P, Tüting C et al. 2022. Reconstitution of 3′ end processing of mammalian pre-mRNA reveals a central role of RBBP6. Genes Dev. 36:195–209
    [Google Scholar]
  12. 12.
    Hill CH, Boreikaitė V, Kumar A, Casañal A, Kubík P et al. 2019. Activation of the endonuclease that defines mRNA 3′ ends requires incorporation into an 8-subunit core cleavage and polyadenylation factor complex. Mol. Cell 73:1217–31
    [Google Scholar]
  13. 13.
    Skolnik-David H, Moore CL, Sharp PA. 1987. Electrophoretic separation of polyadenylation-specific complexes. Genes Dev. 3:672–82
    [Google Scholar]
  14. 14.
    Humphrey T, Christofori G, Lucijanic V, Keller W. 1987. Cleavage and polyadenylation of messenger RNA precursors in vitro occurs within large and specific 3′ processing complexes. EMBO J. 6:4159–68
    [Google Scholar]
  15. 15.
    Takagaki Y, Ryner LC, Manley JL. 1988. Separation and characterization of a poly(A) polymerase and a cleavage/specificity factor required for pre-mRNA polyadenylation. Cell 52:731–42
    [Google Scholar]
  16. 16.
    Bienroth S, Wahle E, Suter-Crazzolara C, Keller W. 1991. Purification and characterization of the cleavage and polyadenylation specificity factor involved in the 3′ processing of messenger RNA precursors. J. Biol. Chem. 266:19768–76
    [Google Scholar]
  17. 17.
    Chan SL, Huppertz I, Yao C, Weng L, Moresco JJ et al. 2014. CPSF30 and Wdr33 directly bind to AAUAAA in mammalian mRNA 3′ processing. Genes Dev. 28:2370–80
    [Google Scholar]
  18. 18.
    Gavin A-C, Krause R, Grandi P, Marzioch M, Bauer A et al. 2002. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415:141–47
    [Google Scholar]
  19. 19.
    Preker PJ, Ohnacker M, Minvielle-Sebastia L, Keller W. 1997. A multisubunit 3′ end processing factor from yeast containing poly(A) polymerase and homologues of the subunits of mammalian cleavage and polyadenylation specificity factor. EMBO J. 16:4727–37
    [Google Scholar]
  20. 20.
    Schönemann L, Kühn U, Martin G, Schäfer P, Gruber AR et al. 2014. Reconstitution of CPSF active in polyadenylation: recognition of the polyadenylation signal by WDR33. Genes Dev. 28:2381–93
    [Google Scholar]
  21. 21.
    Sun Y, Zhang Y, Hamilton K, Manley JL, Shi Y et al. 2018. Molecular basis for the recognition of the human AAUAAA polyadenylation signal. PNAS 115:1419–28
    [Google Scholar]
  22. 22.
    Clerici M, Faini M, Aebersold R, Jinek M. 2017. Structural insights into the assembly and polyA signal recognition mechanism of the human CPSF complex. eLife 6:e33111
    [Google Scholar]
  23. 23.
    Clerici M, Faini M, Muckenfuss LM, Aebersold R, Jinek M. 2018. Structural basis of AAUAAA polyadenylation signal recognition by the human CPSF complex. Nat. Struct. Mol. Biol. 25:135–38
    [Google Scholar]
  24. 24.
    Kumar A, Yu CWH, Rodríguez-Molina JB, Li X-H, Freund SMV, Passmore LA. 2021. Dynamics in Fip1 regulate eukaryotic mRNA 3′ end processing. Genes Dev. 35:1510–26
    [Google Scholar]
  25. 25.
    Hamilton K, Tong L. 2020. Molecular mechanism for the interaction between human CPSF30 and hFip1. Genes Dev. 34:1753–61
    [Google Scholar]
  26. 26.
    Muckenfuss LM, Herranz ACM, Boneberg FM, Clerici M, Jinek M. 2022. Fip1 is a multivalent interaction scaffold for processing factors in human mRNA 3′ end biogenesis. eLife 11:e80332
    [Google Scholar]
  27. 27.
    Proudfoot NJ, Brownlee GG. 1976. 3′ non-coding region sequences in eukaryotic messenger RNA. Nature 263:211–14
    [Google Scholar]
  28. 28.
    Tian B, Graber JH. 2012. Signals for pre-mRNA cleavage and polyadenylation. WIREs RNA 3:385–96
    [Google Scholar]
  29. 29.
    Hamilton K, Sun Y, Tong L. 2019. Biophysical characterizations of the recognition of the AAUAAA polyadenylation signal. RNA 25:1673–80
    [Google Scholar]
  30. 30.
    Sheets MD, Ogg SC, Wickens MP. 1990. Point mutations in AAUAAA and the poly(A) addition site: effects on the accuracy and efficiency of cleavage and polyadenylation in vitro. Nucleic Acids Res. 18:5799–805
    [Google Scholar]
  31. 31.
    Beaudoing E, Freier S, Wyatt JR, Claverie JM, Gautheret D. 2000. Patterns of variant polyadenylation signal usage in human genes. Genome Res. 10:1001–10
    [Google Scholar]
  32. 32.
    Keller W, Bienroth S, Lang KM, Christofori G. 1991. Cleavage and polyadenylation factor CPF specifically interacts with the pre-mRNA 3′ processing signal AAUAAA. EMBO J. 10:4241–49
    [Google Scholar]
  33. 33.
    Rodriguez JB, O'Reilly FJ, Fagarasan H, Sheekey E, Maslen S et al. 2022. Mpe1 senses the binding of pre-mRNA and controls 3′ end processing by CPF. Mol. Cell 82:2490–504
    [Google Scholar]
  34. 34.
    Balbo PB, Bohm A. 2007. Mechanism of poly(A) polymerase: structure of the enzyme-MgATP-RNA ternary complex and kinetic analysis. Structure 15:1117–31
    [Google Scholar]
  35. 35.
    Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. 2004. Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J. 23:616–26
    [Google Scholar]
  36. 36.
    Meinke G, Ezeokonkwo C, Balbo P, Stafford W, Moore C, Bohm A. 2008. Structure of yeast poly(A) polymerase in complex with a peptide from Fip1, an intrinsically-disordered protein. Biochemistry 148:825–32
    [Google Scholar]
  37. 37.
    Ezeokonkwo C, Zhelkovsky A, Lee R, Bohm A, Moore CL. 2011. A flexible linker region in Fip1 is needed for efficient mRNA polyadenylation. RNA 17:652–64
    [Google Scholar]
  38. 38.
    Mandel CR, Kaneko S, Zhang H, Gebauer D, Vethantham V et al. 2006. Polyadenylation factor CPSF-73 is the pre-mRNA 3′-end-processing endonuclease. Nature 444:953–56
    [Google Scholar]
  39. 39.
    Kolev NG, Yario TA, Benson E, Steitz JA 2008. Conserved motifs in both CPSF73 and CPSF100 are required to assemble the active endonuclease for histone mRNA 3′-end maturation. EMBO Rep. 9:1013–18
    [Google Scholar]
  40. 40.
    Sullivan KD, Steiniger M, Marzluff WF. 2009. A core complex of CPSF73, CPSF100, and symplekin may form two different cleavage factors for processing of poly(A) and histone mRNAs. Mol. Cell 34:322–32
    [Google Scholar]
  41. 41.
    Skrajna A, Yang X-C, Dadlez M, Marzluff WF, Dominski Z. 2018. Protein composition of catalytically active U7-dependent processing complexes assembled on histone pre-mRNA containing biotin and a photo-cleavable linker. Nucleic Acids Res. 46:4752–70
    [Google Scholar]
  42. 42.
    Albrecht TR, Shevtsov SP, Wu Y, Mascibroda LG, Peart NJ et al. 2018. Integrator subunit 4 is a ‘Symplekin-like’ scaffold that associates with INTS9/11 to form the Integrator cleavage module. Nucleic Acids Res. 46:4241–55
    [Google Scholar]
  43. 43.
    Pfleiderer MM, Galej WP. 2021. Structure of the catalytic core of the Integrator complex. Mol. Cell 81:1246–59
    [Google Scholar]
  44. 44.
    Wu Y, Albrecht TR, Baillat D, Wagner EJ, Tong L. 2017. Molecular basis for the interaction between Integrator subunits IntS9 and IntS11 and its functional importance. PNAS 114:4394–99
    [Google Scholar]
  45. 45.
    Sun Y, Zhang Y, Aik WS, Yang XC, Marzluff WF et al. 2020. Structure of an active human histone pre-mRNA 3′-end processing machinery. Science 367:700–3
    [Google Scholar]
  46. 46.
    Cossa G, Parua PK, Eilers M, Fisher RP. 2021. Protein phosphatases in the RNAPII transcription cycle: erasers, sculptors, gatekeepers, and potential drug targets. Genes Dev. 35:658–76
    [Google Scholar]
  47. 47.
    Schreieck A, Easter AD, Etzold S, Wiederhold K, Lidschreiber M et al. 2014. RNA polymerase II termination involves C-terminal-domain tyrosine dephosphorylation by CPF subunit Glc7. Nat. Struct. Mol. Biol. 21:175–79
    [Google Scholar]
  48. 48.
    Larame L, Forest A, Bataille AR, Bergeron M, Hanes SD. 2012. A universal RNA polymerase II CTD cycle is orchestrated by complex interplays between kinase, phosphatase, and isomerase enzymes along genes. Mol. Cell 45:158–70
    [Google Scholar]
  49. 49.
    Parua PK, Booth GT, Sansó M, Benjamin B, Tanny JC et al. 2018. A Cdk9–PP1 switch regulates the elongation-termination transition of RNA polymerase II. Nature 558:460–64
    [Google Scholar]
  50. 50.
    Krishnamurthy S, He X, Reyes-Reyes M, Moore C, Hampsey M. 2004. Ssu72 is an RNA polymerase II CTD phosphatase. Mol. Cell 14:387–94
    [Google Scholar]
  51. 51.
    Glover-Cutter K, Kim S, Espinosa J, Bentley DL. 2008. RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nat. Struct. Mol. Biol. 15:71–78
    [Google Scholar]
  52. 52.
    Xiang K, Nagaike T, Xiang S, Kilic T, Beh MM et al. 2010. Crystal structure of the human symplekin–Ssu72–CTD phosphopeptide complex. Nature 467:729–33
    [Google Scholar]
  53. 53.
    Cortazar MA, Sheridan RM, Erickson B, Fong N, Glover-Cutter K et al. 2019. Control of RNA Pol II speed by PNUTS-PP1 and Spt5 dephosphorylation facilitates termination by a “sitting duck torpedo” mechanism. Mol. Cell 76:896–908
    [Google Scholar]
  54. 54.
    Lee JH, You J, Dobrota E, Skalnik DG. 2010. Identification and characterization of a novel human PP1 phosphatase complex. J. Biol. Chem. 285:24466–76
    [Google Scholar]
  55. 55.
    Lidschreiber M, Easter AD, Battaglia S, Rodríguez-Molina JB, Casañal A et al. 2018. The APT complex is involved in non-coding RNA transcription and is distinct from CPF. Nucleic Acids Res. 46:11528–38
    [Google Scholar]
  56. 56.
    Porrua O, Libri D. 2015. Transcription termination and the control of the transcriptome: why, where and how to stop. Nat. Rev. Mol. Cell Biol. 16:190–202
    [Google Scholar]
  57. 57.
    Baillat D, Hakimi M, Näär AM, Shilatifard A, Cooch N et al. 2005. Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell 123:265–76
    [Google Scholar]
  58. 58.
    Elrod ND, Henriques T, Huang KL, Tatomer DC, Wilusz JE et al. 2019. The integrator complex attenuates promoter-proximal transcription at protein-coding genes. Mol. Cell 76:738–52
    [Google Scholar]
  59. 59.
    Zheng H, Qi Y, Hu S, Cao X, Xu C et al. 2020. Identification of Integrator-PP2A complex (INTAC), an RNA polymerase II phosphatase. Science 370:eabb5872
    [Google Scholar]
  60. 60.
    Huang K, Jee D, Stein CB, Elrod ND, Henriques T et al. 2020. Integrator recruits protein phosphatase 2A to prevent pause release and facilitate transcription termination. Mol. Cell 80:345–58
    [Google Scholar]
  61. 61.
    Vervoort SJ, Welsh SA, Devlin JR, Barbieri E, Knight DA et al. 2021. The PP2A-Integrator-CDK9 axis fine-tunes transcription and can be targeted therapeutically in cancer. Cell 184:3143–62
    [Google Scholar]
  62. 62.
    Fianu I, Chen Y, Dienemann C, Dybkov O, Linden A et al. 2021. Structural basis of Integrator-mediated transcription regulation. Science 374:883–87
    [Google Scholar]
  63. 63.
    de Vries H, Rüegsegger U, Hübner W, Friedlein A, Langen H, Keller W. 2000. Human pre-mRNA cleavage factor IIm contains homologs of yeast proteins and bridges two other cleavage factors. EMBO J. 19:5895–904
    [Google Scholar]
  64. 64.
    Christofori G, Keller W. 1988. 3′ cleavage and polyadenylation of mRNA precursors in vitro requires a poly(A) polymerase, a cleavage factor, and a snRNP. Cell 54:875–89
    [Google Scholar]
  65. 65.
    Rüegsegger U, Blank D, Keller W. 1998. Human pre-mRNA cleavage factor Im is related to spliceosomal SR proteins and can be reconstituted in vitro from recombinant subunits. Mol. Cell 1:243–53
    [Google Scholar]
  66. 66.
    Gordon JMB, Shikov S, Kuehner JN, Liriano M, Lee E et al. 2011. Reconstitution of CF IA from overexpressed subunits reveals stoichiometry and provides insights into molecular topology. Biochemistry 50:10203–14
    [Google Scholar]
  67. 67.
    Gross S, Moore C. 2001. Five subunits are required for reconstitution of the cleavage and polyadenylation activities of Saccharomyces cerevisiae cleavage factor I. PNAS 98:6080–85
    [Google Scholar]
  68. 68.
    Yang W, Hsu PL, Yang F, Song JE, Varani G. 2018. Reconstitution of the CstF complex unveils a regulatory role for CstF-50 in recognition of 3′-end processing signals. Nucleic Acids Res. 46:493–503
    [Google Scholar]
  69. 69.
    Schäfer P, Tüting C, Schönemann L, Kühn U, Treiber T et al. 2018. Reconstitution of mammalian cleavage factor II involved in 3′ processing of mRNA precursors. RNA 24:1721–37
    [Google Scholar]
  70. 70.
    Pérez Cañadillas JM, Varani G 2003. Recognition of GU-rich polyadenylation regulatory elements by human CstF-64 protein. EMBO J. 22:2821–30
    [Google Scholar]
  71. 71.
    Ruepp M-D, Schweingruber C, Kleinschmidt N, Schumperli D. 2011. Interactions of CstF-64, CstF-77, and symplekin: implications on localisation and function. Mol. Biol. Cell 22:91–104
    [Google Scholar]
  72. 72.
    Ghazy MA, Gordon JMB, Lee SD, Singh BN, Bohm A et al. 2012. The interaction of Pcf11 and Clp1 is needed for mRNA 3′-end formation and is modulated by amino acids in the ATP-binding site. Nucleic Acids Res. 40:1214–25
    [Google Scholar]
  73. 73.
    Zhang Z, Fu J, Gilmour DS. 2005. CTD-dependent dismantling of the RNA polymerase II elongation complex by the pre-mRNA 3′-end processing factor, Pcf11. Genes Dev. 19:1572–80
    [Google Scholar]
  74. 74.
    Ramirez A, Shuman S, Schwer B. 2008. Human RNA 5′-kinase (hClp1) can function as a tRNA splicing enzyme in vivo. RNA 14:1737–45
    [Google Scholar]
  75. 75.
    Di Giammartino DC, Li W, Ogami K, Yashinskie JJ, Hoque M et al. 2014. RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs. Genes Dev. 28:2248–60
    [Google Scholar]
  76. 76.
    Saijo M, Sakai Y, Kishino T, Niikawa N, Matsuura Y et al. 1995. Molecular cloning of a human protein that binds to the retinoblastoma proteins and chromosomal mapping. Genomics 27:511–19
    [Google Scholar]
  77. 77.
    Sakai Y, Saijo M, Coelho K, Kishino T, Nikawa N, Taya Y. 1995. cDNA sequence and chromosomal localization of a novel human protein, RBQ-1 (RBBP6), that binds to the retinoblastoma gene product. Genomics 30:98–101
    [Google Scholar]
  78. 78.
    Simons A, Melamed-Bessudo C, Wolkowicz R, Sperling J, Sperling R et al. 1997. PACT: cloning and characterization of a cellular p53 binding protein that interacts with Rb. Oncogene 14:145–55
    [Google Scholar]
  79. 79.
    Zhu Y, Wang X, Forouzmand E, Jeong J, Qiao F et al. 2018. Molecular mechanisms for CFIm-mediated regulation of mRNA alternative polyadenylation. Mol. Cell 69:62–74
    [Google Scholar]
  80. 80.
    Turtola M, Manav CM, Kumar A, Tudek A, Mroczek S et al. 2021. Three-layered control of mRNA poly(A) tail synthesis in Saccharomyces cerevisiae. Genes Dev. 35:1290–303
    [Google Scholar]
  81. 81.
    Wahle E. 1995. PolyA tail length control is caused by termination of processive synthesis. J. Biol. Chem. 270:2800–8
    [Google Scholar]
  82. 82.
    Stewart M. 2019. Polyadenylation and nuclear export of mRNAs. J. Biol. Chem. 294:2977–87
    [Google Scholar]
  83. 83.
    Bresson SM, Hunter OV, Hunter AC, Conrad NK. 2015. Canonical poly(A) polymerase activity promotes the decay of a wide variety of mammalian nuclear RNAs. PLOS Genet. 11:e1005610
    [Google Scholar]
  84. 84.
    Bresson SM, Conrad NK. 2013. The human nuclear poly(A)-binding protein promotes RNA hyperadenylation and decay. PLOS Genet. 9:e1003893
    [Google Scholar]
  85. 85.
    Kühn U, Gündel M, Knoth A, Kerwitz Y, Rüdel S, Wahle E. 2009. Poly(A) tail length is controlled by the nuclear poly(A)-binding protein regulating the interaction between poly(A) polymerase and the cleavage and polyadenylation specificity factor. J. Biol. Chem. 284:22803–14
    [Google Scholar]
  86. 86.
    Whitfield ML, Zheng L, Baldwin A, Ohta T, Hurt MM, Marzluff WF. 2000. Stem-loop binding protein, the protein that binds the 3′ end of histone mRNA, is cell cycle regulated by both translational and posttranslational mechanisms. Mol. Cell. Biol. 20:4188–98
    [Google Scholar]
  87. 87.
    Sullivan KD, Mullen TE, Marzluff WF, Wagner EJ. 2009. Knockdown of SLBP results in nuclear retention of histone mRNA. RNA 73:459–72
    [Google Scholar]
  88. 88.
    Sanchez R, Marzluff WF. 2002. The stem-loop binding protein is required for efficient translation of histone mRNA in vivo and in vitro. Mol. Cell. Biol. 22:7093–104
    [Google Scholar]
  89. 89.
    Yang X-C, Sabath I, Debski J, Kaus-Drobek M, Dadlez M et al. 2013. A complex containing the CPSF73 endonuclease and other polyadenylation factors associates with U7 snRNP and is recruited to histone pre-mRNA for 3′-end processing. Mol. Cell. Biol. 33:28–37
    [Google Scholar]
  90. 90.
    Zheng H, Jin Q, Qi Y, Liu W, Ren Y et al. 2021. Structural basis of INTAC-regulated transcription. bioRxiv 2021.11.29.470345. https://doi.org/10.1101/2021.11.29.470345
  91. 91.
    Ozsolak F, Kapranov P, Foissac S, Kim SW, Fishilevich E et al. 2010. Comprehensive polyadenylation site maps in yeast and human reveal pervasive alternative polyadenylation. Cell 143:1018–29
    [Google Scholar]
  92. 92.
    Garneau NL, Wilusz J, Wilusz CJ. 2007. The highways and byways of mRNA decay. Nat. Rev. Mol. Cell Biol. 8:113–26
    [Google Scholar]
  93. 93.
    Carminati M, Manav MC, Bellini D, Passmore LA. 2022. A direct interaction between CPF and Pol II links RNA 3′-end processing to transcription. bioRxiv 2022.07.28.501803. https://doi.org/10.1101/2022.07.28.501803
    [Crossref]
  94. 94.
    An JJ, Gharami K, Liao G, Woo NH, Lau AG et al. 2008. Distinct role of long 3′ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell 134:175–87
    [Google Scholar]
  95. 95.
    Berkovits BD, Mayr C. 2015. Alternative 3′ UTRs act as scaffolds to regulate membrane protein localization. Nature 522:363–67
    [Google Scholar]
  96. 96.
    Tang P, Yang Y, Li G, Huang L, Wen M et al. 2022. Alternative polyadenylation by sequential activation of distal and proximal PolyA sites. Nat. Struct. Mol. Biol. 29:21–31
    [Google Scholar]
  97. 97.
    Ransom B, Goldman SA, Meldolesi J, Zhou L, Murai KK et al. 2008. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 20:1643–48
    [Google Scholar]
  98. 98.
    Ji Z, Tian B 2009. Reprogramming of 3′ untranslated regions of mRNAs by alternative polyadenylation in generation of pluripotent stem cells from different cell types. PLOS ONE 4:e8419
    [Google Scholar]
  99. 99.
    Takagaki Y, Manley JL. 1998. Levels of polyadenylation factor CstF-64 control IgM heavy chain mRNA accumulation and other events associated with B cell differentiation. Mol. Cell 2:761–71
    [Google Scholar]
  100. 100.
    Audibert A, Simonelig M. 1998. Autoregulation at the level of mRNA 3′ end formation of the suppressor of forked gene of Drosophila melanogaster is conserved in Drosophila virilis. PNAS 95:14302–7
    [Google Scholar]
  101. 101.
    Kamieniarz-Gdula K, Gdula MR, Panser K, Nojima T, Monks J et al. 2019. Selective roles of vertebrate PCF11 in premature and full-length transcript termination. Mol. Cell 74:158–72
    [Google Scholar]
  102. 102.
    So BR, Di C, Cai Z, Venters CC, Guo J et al. 2019. A complex of U1 snRNP with cleavage and polyadenylation factors controls telescripting, regulating mRNA transcription in human cells. Mol. Cell 76:590–99
    [Google Scholar]
  103. 103.
    Ran Y, Deng Y, Yao C. 2021. U1 snRNP telescripting: molecular mechanisms and beyond. RNA Biol. 18:1512–23
    [Google Scholar]
  104. 104.
    Cugusi S, Mitter R, Kelly GP, Walker J, Han Z et al. 2021. Heat shock induces premature transcript termination and reconfigures the human transcriptome. Mol. Cell 82:1573–88
    [Google Scholar]
  105. 105.
    Curinha A, Braz SO, Pereira-Castro I, Cruz A, Moreira A 2014. Implications of polyadenylation in health and disease. Nucleus 5:508–19
    [Google Scholar]
  106. 106.
    Higgs DR, Goodbourn SE, Lamb J, Clegg JB, Weatherall DJ, Proudfoot NJ. 1983. α-thalassaemia caused by a polyadenylation signal mutation. Nature 306:5941398–400
    [Google Scholar]
  107. 107.
    Liu H, Moore CL. 2021. On the cutting edge: regulation and therapeutic potential of the mRNA 3′ end nuclease. Trends Biochem. Sci. 46:772–84
    [Google Scholar]
  108. 108.
    Kakegawa J, Sakane N, Suzuki K, Yoshida T. 2019. JTE-607, a multiple cytokine production inhibitor, targets CPSF3 and inhibits pre-mRNA processing. Biochem. Biophys. Res. Commun. 518:32–37
    [Google Scholar]
  109. 109.
    Ross NT, Lohmann F, Carbonneau S, Fazal A, Weihofen WA et al. 2020. CPSF3-dependent pre-mRNA processing as a druggable node in AML and Ewing's sarcoma. Nat. Chem. Biol. 16:50–59
    [Google Scholar]
  110. 110.
    Palencia A, Bougdour A, Brenier-Pinchart M, Touquet B, Bertini R et al. 2017. Targeting Toxoplasma gondii CPSF3 as a new approach to control toxoplasmosis. EMBO Mol. Med. 9:385–94
    [Google Scholar]
  111. 111.
    Swale C, Bougdour A, Gnahoui-David A, Tottey J, Georgeault S et al. 2019. Metal-captured inhibition of pre-mRNA processing activity by CPSF3 controls Cryptosporidium infection. Sci. Transl. Med. 11:eaax7161
    [Google Scholar]
  112. 112.
    Sonoiki E, Ng CL, Lee MCS, Guo D, Zhang YK et al. 2017. A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue. Nat. Commun. 8:14574
    [Google Scholar]
  113. 113.
    Alahmari AA, Chaubey AH, Tisdale AA, Schwarz CD, Cornwell AC et al. 2022. CPSF3 inhibition blocks pancreatic cancer cell proliferation through disruption of core histone processing. bioRxiv 2022.05.09.491230. https://doi.org/10.1101/2022.05.09.491230
  114. 114.
    Ning YUE, Liu W, Guan X, Xie X, Zhang Y. 2019. CPSF3 is a promising prognostic biomarker and predicts recurrence of non-small cell lung cancer. Oncol. Lett. 18:2835–44
    [Google Scholar]
  115. 115.
    Grosso AR, Leite AP, Matos MR, Martins FB, Desterro JMP, Carmo-Fonseca M. 2015. Pervasive transcription read-through promotes aberrant expression of oncogenes and RNA chimeras in renal carcinoma. eLife 4:e09214
    [Google Scholar]
  116. 116.
    Gutierrez PA, Baughman K, Sun Y, Tong L. 2021. A real-time fluorescence assay for CPSF73, the nuclease for pre-mRNA 3′-end processing. RNA 27:1148–54
    [Google Scholar]
  117. 117.
    Wang X, Hennig T, Whisnant AW, Erhard F, Prusty BK et al. 2020. Herpes simplex virus blocks host transcription termination via the bimodal activities of ICP27. Nat. Commun. 11:293
    [Google Scholar]
  118. 118.
    Zhao N, Sebastiano V, Moshkina N, Mena N, Hultquist J et al. 2018. Influenza virus infection causes global RNAPII termination defects. Nat. Struct. Mol. Biol. 25:885–93
    [Google Scholar]
  119. 119.
    Nemeroff ME, Barabino SML, Li Y, Keller W, Krug RM. 1998. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3′ end formation of cellular pre-mRNAs. Mol. Cell 1:991–1000
    [Google Scholar]
  120. 120.
    Das K, Ma L-C, Xiao R, Radvansky B, Aramini J et al. 2008. Structural basis for suppression of a host antiviral response by influenza A virus. PNAS 105:13093–98
    [Google Scholar]
  121. 121.
    Vilborg A, Sabath N, Wiesel Y, Nathans J, Levy-Adam F et al. 2017. Comparative analysis reveals genomic features of stress-induced transcriptional readthrough. PNAS 114:8362–71
    [Google Scholar]
  122. 122.
    Rodríguez-Molina JB, West S, Passmore LA 2023. Knowing when to stop: Transcription termination on protein-coding genes by eukaryotic RNAPII. Mol. Cell 83:3404–15
    [Google Scholar]
  123. 123.
    Eaton JD, Davidson L, Bauer DLV, Natsume T, Kanemaki MT, West S. 2018. Xrn2 accelerates termination by RNA polymerase II, which is underpinned by CPSF73 activity. Genes Dev. 32:127–39
    [Google Scholar]
  124. 124.
    Zhang H, Rigo F, Martinson HG. 2015. Poly(A) signal-dependent transcription termination occurs through a conformational change mechanism that does not require cleavage at the article poly(A) site. Mol. Cell 59:437–48
    [Google Scholar]
  125. 125.
    West S, Proudfoot NJ, Dye MJ. 2008. Molecular dissection of mammalian RNA polymerase II transcriptional termination. Mol. Cell 29:600–10
    [Google Scholar]
  126. 126.
    McCracken S, Fong N, Yankulov K, Ballantyre S, Pan G et al. 1997. The C-terminal domain of RNA polymerase II couples mRNA processing to transcription. Nature 385:357–61
    [Google Scholar]
  127. 127.
    Morgan M, Shiekhattar R, Shilatifard A, Lauberth SM. 2022. It's a DoG-eat-DoG world—altered transcriptional mechanisms drive downstream-of-gene (DoG) transcript production. Mol. Cell 82:1981–91
    [Google Scholar]
  128. 128.
    Rosa-Mercado NA, Zimmer JT, Apostolidi M, Rinehart J, Simon MD et al. 2021. Hyperosmotic stress alters the RNA polymerase II interactome and induces readthrough transcription despite widespread transcriptional repression. Mol. Cell 81:502–13
    [Google Scholar]
  129. 129.
    Lykke-Andersen S, Zumer K, Schmid M, Cramer P. 2021. Integrator is a genome-wide attenuator of non-productive transcription. Mol. Cell 81:514–29
    [Google Scholar]
  130. 130.
    Vilborg A, Passarelli MC, Yario TA, Tycowski KT, Steitz JA. 2015. Widespread inducible transcription downstream of human genes. Mol. Cell 59:449–61
    [Google Scholar]
  131. 131.
    Palmer AC, Egan JB, Shearwin KE. 2011. Transcriptional interference by RNA polymerase pausing and dislodgement of transcription factors. Transcription 2:9–14
    [Google Scholar]
  132. 132.
    David L, Huber W, Granovskaia M, Toedling J, Palm CJ et al. 2006. A high-resolution map of transcription in the yeast genome. PNAS 103:5320–25
    [Google Scholar]
  133. 133.
    Reimer KA, Mimoso CA, Adelman K, Neugebauer KM, Reimer KA et al. 2021. Co-transcriptional splicing regulates 3′-end cleavage during mammalian erythropoiesis. Mol. Cell 81:998–1012
    [Google Scholar]
  134. 134.
    Drexler HL, Choquet K, Churchman LS. 2020. Splicing kinetics and coordination revealed by direct nascent RNA sequencing through nanopores. Mol. Cell 77:985–98
    [Google Scholar]
  135. 135.
    Herzel L, Straube K, Neugebauer KM. 2018. Long-read sequencing of nascent RNA reveals coupling among RNA processing events. Genome Res. 28:1008–19
    [Google Scholar]
  136. 136.
    Sousa-Luís R, Dujardin G, Zukher I, Kimura H, Weldon C et al. 2021. POINT technology illuminates the processing of polymerase-associated intact nascent transcripts. Mol. Cell 81:1935–50
    [Google Scholar]
  137. 137.
    Zhang S, Aibara S, Vos SM, Agafonov DE. 2021. Structure of a transcribing RNA polymerase II-U1 snRNP complex. Science 371:305–9
    [Google Scholar]
/content/journals/10.1146/annurev-biochem-052521-012445
Loading
/content/journals/10.1146/annurev-biochem-052521-012445
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error