Browse > Article
http://dx.doi.org/10.14348/molcells.2016.0035

Alternative Polyadenylation of mRNAs: 3'-Untranslated Region Matters in Gene Expression  

Yeh, Hsin-Sung (Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota)
Yong, Jeongsik (Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota)
Abstract
Almost all of eukaryotic mRNAs are subjected to polyadenylation during mRNA processing. Recent discoveries showed that many of these mRNAs contain more than one polyadenylation sites in their 3' untranslated regions (UTR) and that alternative polyadenylation (APA) is prevalent among these genes. Many biological processes such as differentiation, proliferation, and tumorigenesis have been correlated to global APA events in the 3' UTR of mRNAs, suggesting that these APA events are tightly regulated and may play important physiological roles. In this review, recent discoveries in the physiological roles of APA events, as well as the known and proposed mechanisms are summarized. Perspective for future directions is also discussed.
Keywords
3' UTR; 3'-end processing; alternative polyadenylation; mTOR; post-transcriptional gene regulation;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Kuhn, U., Gundel, M., Knoth, A., Kerwitz, Y., Rüdel, 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.   DOI
2 Laplante, M., and Sabatini, D. (2012). mTOR signaling in growth control and disease. Cell 149, 274-293.   DOI
3 Lembo, A., Di Cunto, F., and Provero, P. (2012). Shortening of 3 UTRs correlates with poor prognosis in breast and lung cancer. PLoS One 7, e31129.   DOI
4 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.   DOI
5 Licatalosi, D.D., Mele, A., Fak, J.J., Ule, J., Kayikci, M., Chi, S.W., Clark, T.A., Schweitzer, A.C., Blume, J.E., Wang, X., et al. (2008). HITS-CLIP yields genome-wide insights into brain alternative RNA processing. Nature 456, 464-469.   DOI
6 Martin, G., Gruber, A., Keller, W., and Zavolan, M. (2012). Genomewide analysis of pre-mRNA 3' end processing reveals a decisive role of human cleavage factor I in the regulation of 3' UTR length. Cell Rep. 1, 753-763.   DOI
7 Masamha, C.P., Xia, Z., Yang, J., Albrecht, T.R., Li, M., Shyu, A., Li, W., and Wagner, E.J. (2014). CFIm25 links alternative polyadenylation to glioblastoma tumour suppression. Nature 510, 412-416.   DOI
8 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.   DOI
9 Millevoi, S., Loulergue, C., Dettwiler, S., Karaa, S.Z., Keller, W., Antoniou, M., and Vagner, S. (2006). An interaction between U2AF 65 and CF Im links the splicing and 3ae end processing machineries. EMBO J. 25, 4854-4864.   DOI
10 Morris, A.R., Bos, A., Diosdado, B., Rooijers, K., Elkon, R., Bolijn, A.S., Carvalho, B., Meijer, G.A., and Agami, R. (2012). Alternative cleavage and polyadenylation during colorectal cancer development. Clin. Cancer Res. 18, 5256-5266.   DOI
11 Proudfoot, N.J. (2011). Ending the message: poly(A) signals then and now. Genes Dev. 25, 1770-1782.   DOI
12 Sandberg, R., Neilson, J., Sarma, A., Sharp, P., and Burge, C. (2008a). Proliferating cells express mRNAs with shortened 3' untranslated regions and fewer microRNA target sites. Science (New York, N.Y.) 320, 1643-1647.   DOI
13 Sandberg, R., Neilson, J.R., Sarma, A., Sharp, P.A., and Burge, C.B. (2008b). Proliferating cells express mRNAs with shortened 3' untranslated regions and fewer microRNA target sites. Science 320, 1643-1647.   DOI
14 Singh, P., Alley, T.L., Wright, S.M., Kamdar, S., Schott, W., Wilpan, R.Y., Mills, K.D., and Graber, J.H. (2009). Global changes in processing of mRNA 3' untranslated regions characterize clinically distinct cancer subtypes. Cancer Res. 69, 9422-9430.   DOI
15 Takagaki, Y., Seipelt, R.L., Peterson, M.L., and Manley, J.L. (1996). The polyadenylation factor CstF-64 regulates alternative processing of IgM heavy chain pre-mRNA during B cell differentiation. Cell 87, 941-952.   DOI
16 Tian, B., and Manley, J.L. (2013). Alternative cleavage and polyadenylation: the long and short of it. Trends Biochem. Sci. 38, 312-320.   DOI
17 Zhang, H., Lee, J., and Tian, B. (2005). Biased alternative polyadenylation in human tissues. Genome Biol. 6, R100.   DOI
18 Wang, E., Cody, N.L., Jog, S., Biancolella, M., Wang, T., Treacy, D., Luo, S., Schroth, G., Housman, D., Reddy, S., et al. (2012). Transcriptome-wide regulation of pre-mRNA splicing and mRNA localization by muscleblind proteins. Cell 150, 710-724.   DOI
19 Yang, Q., Gilmartin, G.M., and Doublie, S. (2010). Structural basis of UGUA recognition by the Nudix protein CFIm25 and implications for a regulatory role in mRNA 3' processing. Proc. Natl. Acad. Sci. USA 107, 10062-10067.   DOI
20 Yao, C., Biesinger, J., Wan, J., Weng, L., Xing, Y., Xie, X., and Shi, Y. (2012). Transcriptome-wide analyses of CstF64-RNA interactions in global regulation of mRNA alternative polyadenylation. Proc. Natl. Acad. Sci. USA 109, 18773-18778.   DOI
21 Zhang, X., Virtanen, A., and Kleiman, F.E. (2010). To polyadenylate or to deadenylate: That is the question. Cell Cycle 9, 4437-4449.   DOI
22 Zhu, H., Zhou, H., Hasman, R.A., and Lou, H. (2007). Hu proteins regulate polyadenylation by blocking sites containing U-rich sequences. J. Biol. Chem. 282, 2203-2210.   DOI
23 Beisang, D., Reilly, C., and Bohjanen, P.R. (2014). Alternative polyadenylation regulates CELF1/CUGBP1 target transcripts following T cell activation. Gene 550, 93-100.   DOI
24 Barabino, S.M.L., and Keller, W. (1999). Last but not least: fegulated Poly(A) tail formation. Cell 99, 9-11.   DOI
25 Bava, F., Eliscovich, C., Ferreira, P.G., Minana, B., Ben-Dov, C., Guigo, R., Valcarcel, J., and Mendez, R. (2013). CPEB1 coordinates alternative 3prime]-UTR formation with translational regulation. Nature 495, 121-125.   DOI
26 Beaudoing, E., Freier, S., Wyatt, J.R., Claverie, J., and Gautheret, D. (2000). Patterns of variant polyadenylation signal usage in human genes. Genome Res. 10, 1001-1010.   DOI
27 Boutet, S., Cheung, T., Quach, N., Liu, L., Prescott, S.L., Edalati, A., Iori, K., and Rando, T. (2012). Alternative polyadenylation mediates microRNA regulation of muscle stem cell function. Cell Stem Cell 10, 327-336.   DOI
28 Colgan, D.F., and Manley, J.L. (1997). Mechanism and regulation of mRNA polyadenylation. Genes Dev. 11, 2755-2766.   DOI
29 Chang, J., Zhang, W., Yeh, H., de Jong, E.P., Jun, S., Kim, K., Bae, S.S., Beckman, K., Hwang, T.H., Kim, K., et al. (2015). mRNA 3prime]-UTR shortening is a molecular signature of mTORC1 activation. Nat. Commun. 6, 7218.
30 Chuvpilo, S., Zimmer, M., Kerstan, A., Glockner, J., Avots, A., Escher, C., Fischer, C., Inashkina, I., Jankevics, E., Berberich- Siebelt, F., et al. (1999). Alternative polyadenylation events contribute to the induction of NF-ATc in effector T cells. Immunity 10, 261-269.   DOI
31 Danckwardt, S., Hentze, M.W., and Kulozik, A.E. (2007a). 3ae end mRNA processing: molecular mechanisms and implications for health and disease. EMBO J. 27, 482-498.
32 Danckwardt, S., Kaufmann, I., Gentzel, M., Foerstner, K.U., Gantzert, A., Gehring, N.H., Neu‐Yilik, G., Bork, P., Keller, W., Wilm, M., et al. (2007b). Splicing factors stimulate polyadenylation via USEs at non‐canonical 3′ end formation signals. EMBO J. 26, 2658-2669.   DOI
33 de Klerk, E., Venema, A., Anvar, S.Y., Goeman, J.J., Hu, O., Trollet, C., Dickson, G., den Dunnen, J.T., van der Maarel, S.M., Raz, V., et al. (2012). Poly(A) binding protein nuclear 1 levels affect alternative polyadenylation. Nucleic Acids Res. 40, 9089-9101.   DOI
34 Di Giammartino, D.C., Nishida, K., and Manley, J.L. (2011). Mechanisms and consequences of alternative polyadenylation. Mol. Cell 43, 853-866.   DOI
35 Elkon, R., Drost, J., van Haaften, G., Jenal, M., Schrier, M., Oude Vrielink, J., and Agami, R. (2012). E2F mediates enhanced alternative polyadenylation in proliferation. Genome Biol. 13, R59.   DOI
36 Han, T., Kato, M., Xie, S., Wu, L., Mirzaei, H., Pei, J., Chen, M., Xie, Y., Allen, J., Xiao, G., et al. (2012). Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. Cell 149, 768-779.   DOI
37 Elkon, R., Ugalde, A.P., and Agami, R. (2013). Alternative cleavage and polyadenylation: extent, regulation and function. Nat. Rev. Genet. 14, 496-506.   DOI
38 Fabian, M.R., Sonenberg, N., and Filipowicz, W. (2010). Regulation of mRNA Translation and Stability by microRNAs. Annu. Rev. Biochem. 79, 351-379.   DOI
39 Graber, J.H., Cantor, C.R., Mohr, S.C., and Smith, T.F. (1999). Genomic detection of new yeast pre-mRNA 3'-end-processing signals. Nucleic Acids Res. 27, 888-894.   DOI
40 Hoque, M., Ji, Z., Zheng, D., Luo, W., Li, W., You, B., Park, J.Y., Yehia, G., and Tian, B. (2013). Analysis of alternative cleavage and polyadenylation by 3prime] region extraction and deep sequencing. Nat. Meth. 10, 133-139.   DOI
41 Jenal, M., Elkon, R., Loayza-Puch, F., van Haaften, G., Kühn, U., Menzies, F., Vrielink, J.F., Bos, A., Drost, J., Rooijers, K., et al. (2012). The poly(A)-binding protein nuclear 1 suppresses alternative cleavage and polyadenylation sites. Cell 149, 538-553.   DOI
42 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.   DOI
43 Ji, Z., Lee, J.Y., Pan, Z., Jiang, B., and Tian, B. (2009). Progressive lengthening of 3' untranslated regions of mRNAs by alternative polyadenylation during mouse embryonic development. Proc. Natl. Acad. Sci. 106, 7028-7033.   DOI