Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Sequential Polyadenylation to Enable Alternative mRNA 3' End Formation

  • Yajing Hao (Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California San Diego) ;
  • Ting Cai (Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California San Diego) ;
  • Chang Liu (Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California San Diego) ;
  • Xuan Zhang (Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California San Diego) ;
  • Xiang-Dong Fu (Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California San Diego)
  • Received : 2022.11.10
  • Accepted : 2022.11.22
  • Published : 2023.01.31
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Abstract

In eukaryotic cells, a key RNA processing step to generate mature mRNA is the coupled reaction for cleavage and polyadenylation (CPA) at the 3' end of individual transcripts. Many transcripts are alternatively polyadenylated (APA) to produce mRNAs with different 3' ends that may either alter protein coding sequence (CDS-APA) or create different lengths of 3'UTR (tandem-APA). As the CPA reaction is intimately associated with transcriptional termination, it has been widely assumed that APA is regulated cotranscriptionally. Isoforms terminated at different regions may have distinct RNA stability under different conditions, thus altering the ratio of APA isoforms. Such differential impacts on different isoforms have been considered as post-transcriptional APA, but strictly speaking, this can only be considered "apparent" APA, as the choice is not made during the CPA reaction. Interestingly, a recent study reveals sequential APA as a new mechanism for post-transcriptional APA. This minireview will focus on this new mechanism to provide insights into various documented regulatory paradigms.

Keywords

Acknowledgement

Y.H., T.C., C.L., and X.Z. were supported by NIH grants HG004659 and DK098808.

References

  1. Beaudoin, J.D. and Perreault, J.P. (2013). Exploring mRNA 3'-UTR G-quadruplexes: evidence of roles in both alternative polyadenylation and mRNA shortening. Nucleic Acids Res. 41, 5898-5911. https://doi.org/10.1093/nar/gkt265
  2. Boehning, M., Dugast-Darzacq, C., Rankovic, M., Hansen, A.S., Yu, T., Marie-Nelly, H., McSwiggen, D.T., Kokic, G., Dailey, G.M., Cramer, P., et al. (2018). RNA polymerase II clustering through carboxy-terminal domain phase separation. Nat. Struct. Mol. Biol. 25, 833-840. https://doi.org/10.1038/s41594-018-0112-y
  3. Chen, S., Wang, R., Zheng, D., Zhang, H., Chang, X., Wang, K., Li, W., Fan, J., Tian, B., and Cheng, H. (2019). The mRNA export receptor NXF1 coordinates transcriptional dynamics, alternative polyadenylation, and mRNA export. Mol. Cell 74, 118-131.e7. https://doi.org/10.1016/j.molcel.2019.01.026
  4. Cheng, L.C., Zheng, D., Baljinnyam, E., Sun, F., Ogami, K., Yeung, P.L., Hoque, M., Lu, C.W., Manley, J.L., and Tian, B. (2020). Widespread transcript shortening through alternative polyadenylation in secretory cell differentiation. Nat. Commun. 11, 3182.
  5. Connelly, S. and Manley, J.L. (1988). A functional mRNA polyadenylation signal is required for transcription termination by RNA polymerase II. Genes Dev. 2, 440-452. https://doi.org/10.1101/gad.2.4.440
  6. Dantonel, J.C., Murthy, K.G., Manley, J.L., and Tora, L. (1997). Transcription factor TFIID recruits factor CPSF for formation of 3' end of mRNA. Nature 389, 399-402. https://doi.org/10.1038/38763
  7. Derti, A., Garrett-Engele, P., Macisaac, K.D., Stevens, R.C., Sriram, S., Chen, R., Rohl, C.A., Johnson, J.M., and Babak, T. (2012). A quantitative atlas of polyadenylation in five mammals. Genome Res. 22, 1173-1183. https://doi.org/10.1101/gr.132563.111
  8. Djebali, S., Davis, C.A., Merkel, A., Dobin, A., Lassmann, T., Mortazavi, A., Tanzer, A., Lagarde, J., Lin, W., Schlesinger, F., et al. (2012). Landscape of transcription in human cells. Nature 489, 101-108. https://doi.org/10.1038/nature11233
  9. Eaton, J.D., Francis, L., Davidson, L., and West, S. (2020). A unified allosteric/ torpedo mechanism for transcriptional termination on human proteincoding genes. Genes Dev. 34, 132-145. https://doi.org/10.1101/gad.332833.119
  10. Elkon, R., Ugalde, A.P., and Agami, R. (2013). Alternative cleavage and polyadenylation: extent, regulation and function. Nat. Rev. Genet. 14, 496-506. https://doi.org/10.1038/nrg3482
  11. Glover-Cutter, K., Kim, S., Espinosa, J., and Bentley, D.L. (2008). RNA polymerase II pauses and associates with pre-mRNA processing factors at both ends of genes. Nat. Struct. Mol. Biol. 15, 71-78. https://doi.org/10.1038/nsmb1352
  12. Gregersen, L.H., Mitter, R., Ugalde, A.P., Nojima, T., Proudfoot, N.J., Agami, R., Stewart, A., and Svejstrup, J.Q. (2019). SCAF4 and SCAF8, mRNA anti-terminator proteins. Cell 177, 1797-1813.e18. https://doi.org/10.1016/j.cell.2019.04.038
  13. Gromak, N., West, S., and Proudfoot, N.J. (2006). Pause sites promote transcriptional termination of mammalian RNA polymerase II. Mol. Cell. Biol. 26, 3986-3996. https://doi.org/10.1128/MCB.26.10.3986-3996.2006
  14. Gruber, A.J. and Zavolan, M. (2019). Alternative cleavage and polyadenylation in health and disease. Nat. Rev. Genet. 20, 599-614. https://doi.org/10.1038/s41576-019-0145-z
  15. Guo, Y.E., Manteiga, J.C., Henninger, J.E., Sabari, B.R., Dall'Agnese, A., Hannett, N.M., Spille, J.H., Afeyan, L.K., Zamudio, A.V., Shrinivas, K., et al. (2019). Pol II phosphorylation regulates a switch between transcriptional and splicing condensates. Nature 572, 543-548. https://doi.org/10.1038/s41586-019-1464-0
  16. Han, J., Xiong, J., Wang, D., and Fu, X.D. (2011). Pre-mRNA splicing: where and when in the nucleus. Trends Cell Biol. 21, 336-343. https://doi.org/10.1016/j.tcb.2011.03.003
  17. Ji, Z. and 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. Kaczmarek Michaels, K., Mohd Mostafa, S., Ruiz Capella, J., and Moore,
  18. C.L. (2020). Regulation of alternative polyadenylation in the yeast Saccharomyces cerevisiae by histone H3K4 and H3K36 methyltransferases. Nucleic Acids Res. 48, 5407-5425. https://doi.org/10.1093/nar/gkaa292
  19. Kuhn, U., Gundel, M., Knoth, A., Kerwitz, Y., Rudel, S., and 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, 22803-22814. https://doi.org/10.1074/jbc.M109.018226
  20. Kwon, B., Fansler, M.M., Patel, N.D., Lee, J., Ma, W., and Mayr, C. (2022). Enhancers regulate 3' end processing activity to control expression of alternative 3'UTR isoforms. Nat. Commun. 13, 2709.
  21. Li, W., You, B., Hoque, M., Zheng, D., Luo, W., Ji, Z., Park, J.Y., Gunderson, S.I., Kalsotra, A., Manley, J.L., et al. (2015). Systematic profiling of poly(A)+transcripts modulated by core 3' end processing and splicing factors reveals regulatory rules of alternative cleavage and polyadenylation. PLoS Genet. 11, e1005166.
  22. Lin, J., Hung, F.Y., Ye, C., Hong, L., Shih, Y.H., Wu, K., and Li, Q.Q. (2020). HDA6-dependent histone deacetylation regulates mRNA polyadenylation in Arabidopsis. Genome Res. 30, 1407-1417. https://doi.org/10.1101/gr.255232.119
  23. Liu, X., Freitas, J., Zheng, D., Oliveira, M.S., Hoque, M., Martins, T., Henriques, T., Tian, B., and Moreira, A. (2017). Transcription elongation rate has a tissue-specific impact on alternative cleavage and polyadenylation in Drosophila melanogaster. RNA 23, 1807-1816. https://doi.org/10.1261/rna.062661.117
  24. Mayr, C. and Bartel, D.P. (2009). Widespread shortening of 3'UTRs by alternative cleavage and polyadenylation activates oncogenes in cancer cells. Cell 138, 673-684. https://doi.org/10.1016/j.cell.2009.06.016
  25. McCracken, S., Fong, N., Yankulov, K., Ballantyne, S., Pan, G., Greenblatt, J., Patterson, S.D., Wickens, M., and Bentley, D.L. (1997). The C-terminal domain of RNA polymerase II couples mRNA processing to transcription. Nature 385, 357-361. https://doi.org/10.1038/385357a0
  26. Mitschka, S. and Mayr, C. (2022). Context-specific regulation and function of mRNA alternative polyadenylation. Nat. Rev. Mol. Cell Biol. 23, 779-796. https://doi.org/10.1038/s41580-022-00507-5
  27. Nagaike, T., Logan, C., Hotta, I., Rozenblatt-Rosen, O., Meyerson, M., and Manley, J.L. (2011). Transcriptional activators enhance polyadenylation of mRNA precursors. Mol. Cell 41, 409-418. https://doi.org/10.1016/j.molcel.2011.01.022
  28. Nanavaty, V., Abrash, E.W., Hong, C., Park, S., Fink, E.E., Li, Z., Sweet, T.J., Bhasin, J.M., Singuri, S., Lee, B.H., et al. (2020). DNA methylation regulates alternative polyadenylation via CTCF and the cohesin complex. Mol. Cell 78, 752-764.e6. https://doi.org/10.1016/j.molcel.2020.03.024
  29. Neve, J., Burger, K., Li, W., Hoque, M., Patel, R., Tian, B., Gullerova, M., and Furger, A. (2016). Subcellular RNA profiling links splicing and nuclear DICER1 to alternative cleavage and polyadenylation. Genome Res. 26, 24-35. https://doi.org/10.1101/gr.193995.115
  30. Niehrs, C. and Luke, B. (2020). Regulatory R-loops as facilitators of gene expression and genome stability. Nat. Rev. Mol. Cell Biol. 21, 167-178. https://doi.org/10.1038/s41580-019-0206-3
  31. Pinto, P.A., Henriques, T., Freitas, M.O., Martins, T., Domingues, R.G., Wyrzykowska, P.S., Coelho, P.A., Carmo, A.M., Sunkel, C.E., Proudfoot, N.J., et al. (2011). RNA polymerase II kinetics in polo polyadenylation signal selection. EMBO J. 30, 2431-2444. https://doi.org/10.1038/emboj.2011.156
  32. Proudfoot, N. (2004). New perspectives on connecting messenger RNA 3' end formation to transcription. Curr. Opin. Cell Biol. 16, 272-278. https://doi.org/10.1016/j.ceb.2004.03.007
  33. Proudfoot, N.J. (2016). Transcriptional termination in mammals: stopping the RNA polymerase II juggernaut. Science 352, aad9926.
  34. Santos-Pereira, J.M. and Aguilera, A. (2015). R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16, 583-597. https://doi.org/10.1038/nrg3961
  35. Shi, Y., Di Giammartino, D.C., Taylor, D., Sarkeshik, A., Rice, W.J., Yates, J.R., 3rd, Frank, J., and Manley, J.L. (2009). Molecular architecture of the human pre-mRNA 3' processing complex. Mol. Cell 33, 365-376. https://doi.org/10.1016/j.molcel.2008.12.028
  36. Shi, Y. and Manley, J.L. (2015). The end of the message: multiple protein-RNA interactions define the mRNA polyadenylation site. Genes Dev. 29, 889-897. https://doi.org/10.1101/gad.261974.115
  37. Skourti-Stathaki, K., Proudfoot, N.J., and Gromak, N. (2011). Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol. Cell 42, 794-805. https://doi.org/10.1016/j.molcel.2011.04.026
  38. Soles, L.V. and Shi, Y. (2021). Crosstalk between mRNA 3'-end processing and epigenetics. Front. Genet. 12, 637705.
  39. Tang, P., Yang, Y., Li, G., Huang, L., Wen, M., Ruan, W., Guo, X., Zhang, C., Zuo, X., Luo, D., et al. (2022). Alternative polyadenylation by sequential activation of distal and proximal PolyA sites. Nat. Struct. Mol. Biol. 29, 21-31. https://doi.org/10.1038/s41594-021-00709-z
  40. Tian, B. and Manley, J.L. (2017). Alternative polyadenylation of mRNA precursors. Nat. Rev. Mol. Cell Biol. 18, 18-30. https://doi.org/10.1038/nrm.2016.116
  41. Wahle, E. (1995). Poly(A) tail length control is caused by termination of processive synthesis. J. Biol. Chem. 270, 2800-2808. https://doi.org/10.1074/jbc.270.6.2800
  42. Wood, A.J., Schulz, R., Woodfine, K., Koltowska, K., Beechey, C.V., Peters, J., Bourc'his, D., and Oakey, R.J. (2008). Regulation of alternative polyadenylation by genomic imprinting. Genes Dev. 22, 1141-1146. https://doi.org/10.1101/gad.473408
  43. Xia, Z., Donehower, L.A., Cooper, T.A., Neilson, J.R., Wheeler, D.A., Wagner, E.J., and Li, W. (2014). Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3'-UTR landscape across seven tumour types. Nat. Commun. 5, 5274.
  44. Xiao, R., Chen, J.Y., Liang, Z., Luo, D., Chen, G., Lu, Z.J., Chen, Y., Zhou, B., Li, H., Du, X., et al. (2019). Pervasive chromatin-RNA binding protein interactions enable RNA-based regulation of transcription. Cell 178, 107-121.e18. https://doi.org/10.1016/j.cell.2019.06.001
  45. Yonaha, M. and Proudfoot, N.J. (1999). Specific transcriptional pausing activates polyadenylation in a coupled in vitro system. Mol. Cell 3, 593-600. https://doi.org/10.1016/S1097-2765(00)80352-4
  46. Yuryev, A., Patturajan, M., Litingtung, Y., Joshi, R.V., Gentile, C., Gebara, M., and Corden, J.L. (1996). The C-terminal domain of the largest subunit of RNA polymerase II interacts with a novel set of serine/arginine-rich proteins. Proc. Natl. Acad. Sci. U. S. A. 93, 6975-6980. https://doi.org/10.1073/pnas.93.14.6975
  47. Zhang, H., Rigo, F., and Martinson, H.G. (2015). Poly(A) signal-dependent transcription termination occurs through a conformational change mechanism that does not require cleavage at the poly(A) site. Mol. Cell 59, 437-448. https://doi.org/10.1016/j.molcel.2015.06.008
  48. Zhou, Y., Li, H.R., Huang, J., Jin, G., and Fu, X.D. (2014). Multiplex analysis of polyA-linked sequences (MAPS): an RNA-seq strategy to profile poly(A+) RNA. Methods Mol. Biol. 1125, 169-178. https://doi.org/10.1007/978-1-62703-971-0_15
  49. Zhu, Y., Wang, X., Forouzmand, E., Jeong, J., Qiao, F., Sowd, G.A., Engelman, A.N., Xie, X., Hertel, K.J., and Shi, Y. (2018). Molecular mechanisms for CFIm-mediated regulation of mRNA alternative polyadenylation. Mol. Cell 69, 62-74.e4.  https://doi.org/10.1016/j.molcel.2017.11.031