Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Controlling nuclear RNA levels

Abstract

RNA turnover is an integral part of cellular RNA homeostasis and gene expression regulation. Whereas the cytoplasmic control of protein-coding mRNA is often the focus of study, we discuss here the less appreciated role of nuclear RNA decay systems in controlling RNA polymerase II (RNAPII)-derived transcripts. Historically, nuclear RNA degradation was found to be essential for the functionalization of transcripts through their proper maturation. Later, it was discovered to also be an important caretaker of nuclear hygiene by removing aberrant and unwanted transcripts. Recent years have now seen a set of new protein complexes handling a variety of new substrates, revealing functions beyond RNA processing and the decay of non-functional transcripts. This includes an active contribution of nuclear RNA metabolism to the overall cellular control of RNA levels, with mechanistic implications during cellular transitions.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Nuclear RNA decay opportunities around protein-coding genes.
Fig. 2: Escaping nuclear decay.
Fig. 3: RNA homeostasis model.

References

  1. 1.

    Mitchell, P., Petfalski, E., Shevchenko, A., Mann, M. & Tollervey, D. The exosome: a conserved eukaryotic RNA processing complex containing multiple 3′-5′ exoribonucleases. Cell 91, 457–466 (1997). The discovery and introductory description of the RNA exosome complex.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Kilchert, C., Wittmann, S. & Vasiljeva, L. The regulation and functions of the nuclear RNA exosome complex. Nat. Rev. Mol. Cell Biol. 17, 227–239 (2016).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Carninci, P. et al. The transcriptional landscape of the mammalian genome. Science 309, 1559–1563 (2005).

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Djebali, S. et al. Landscape of transcription in human cells. Nature 489, 101–108 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. 5.

    Jensen, T. H., Jacquier, A. & Libri, D. Dealing with pervasive transcription. Mol. Cell 52, 473–484 (2013).

    PubMed  Article  CAS  Google Scholar 

  6. 6.

    Preker, P. et al. RNA exosome depletion reveals transcription upstream of active human promoters. Science 322, 1851–1854 (2008). The identification of PROMPTs as major RNA exosome targets in human cells.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Wyers, F. et al. Cryptic pol II transcripts are degraded by a nuclear quality control pathway involving a new poly(A) polymerase. Cell 121, 725–737 (2005). The identification of CUTs as major RNA exosome targets in S. cerevisiae.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Petfalski, E., Dandekar, T., Henry, Y. & Tollervey, D. Processing of the precursors to small nucleolar RNAs and rRNAs requires common components. Mol. Cell. Biol. 18, 1181–1189 (1998).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. 9.

    Muhlemann, O. & Jensen, T. H. mRNP quality control goes regulatory. Trends Genet. 28, 70–77 (2012).

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Arigo, J. T., Carroll, K. L., Ames, J. M. & Corden, J. L. Regulation of yeast NRD1 expression by premature transcription termination. Mol. Cell 21, 641–651 (2006).

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Iasillo, C. et al. ARS2 is a general suppressor of pervasive transcription. Nucleic Acids Res. 45, 10229–10241 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  12. 12.

    Meola, N. et al. Identification of a nuclear exosome decay pathway for processed transcripts. Mol. Cell 64, 520–533 (2016).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Schulz, D. et al. Transcriptome surveillance by selective termination of noncoding RNA synthesis. Cell 155, 1075–1087 (2013).

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Thiebaut, M. et al. Futile cycle of transcription initiation and termination modulates the response to nucleotide shortage in S. cerevisiae. Mol. Cell 31, 671–682 (2008).

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Lubas, M. et al. Interaction profiling identifies the human nuclear exosome targeting complex. Mol. Cell 43, 624–637 (2011).

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Cakiroglu, S. A., Zaugg, J. B. & Luscombe, N. M. Backmasking in the yeast genome: encoding overlapping information for protein-coding and RNA degradation. Nucleic Acids Res. 44, 8065–8072 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Gudipati, R. K., Villa, T., Boulay, J. & Libri, D. Phosphorylation of the RNA polymerase II C-terminal domain dictates transcription termination choice. Nat. Struct. Mol. Biol. 15, 786–794 (2008).

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Jonkers, I. & Lis, J. T. Getting up to speed with transcription elongation by RNA polymerase II. Nat. Rev. Mol. Cell Biol. 16, 167–177 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Henriques, T. et al. Stable pausing by RNA polymerase II provides an opportunity to target and integrate regulatory signals. Mol. Cell 52, 517–528 (2013).

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    Krebs, A. R. et al. Genome-wide single-molecule footprinting reveals high RNA polymerase II turnover at paused promoters. Mol. Cell 67, 411–422.e4 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Valen, E. et al. Biogenic mechanisms and utilization of small RNAs derived from human protein-coding genes. Nat. Struct. Mol. Biol. 18, 1075–1082 (2011).

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    Brannan, K. et al. mRNA decapping factors and the exonuclease Xrn2 function in widespread premature termination of RNA polymerase II transcription. Mol. Cell 46, 311–324 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. 23.

    Berg, M. G. et al. U1 snRNP determines mRNA length and regulates isoform expression. Cell 150, 53–64 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Kaida, D. et al. U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation. Nature 468, 664–668 (2010). A study reporting that PCPA inside gene introns is suppressed by the U1 snRNP.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Oh, J. M. et al. U1 snRNP telescripting regulates a size-function-stratified human genome. Nat. Struct. Mol. Biol. 24, 993–999 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    Chiu, A. C. et al. Transcriptional pause sites delineate stable nucleosome-associated premature polyadenylation suppressed by U1 snRNP. Mol. Cell 69, 648–663.e7 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  27. 27.

    Ashe, M. P., Pearson, L. H. & Proudfoot, N. J. The HIV-1 5′ LTR poly(A) site is inactivated by U1 snRNP interaction with the downstream major splice donor site. EMBO J. 16, 5752–5763 (1997).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  28. 28.

    Ntini, E. et al. Polyadenylation site-induced decay of upstream transcripts enforces promoter directionality. Nat. Struct. Mol. Biol. 20, 923–928 (2013).

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Almada, A. E., Wu, X., Kriz, A. J., Burge, C. B. & Sharp, P. A. Promoter directionality is controlled by U1 snRNP and polyadenylation signals. Nature 499, 360–363 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Seila, A. C. et al. Divergent transcription from active promoters. Science 322, 1849–1851 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    Kaida, D. The reciprocal regulation between splicing and 3ʹ-end processing. Wiley Interdiscip. Rev. RNA 7, 499–511 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  32. 32.

    Andersen, P. R. et al. The human cap-binding complex is functionally connected to the nuclear RNA exosome. Nat. Struct. Mol. Biol. 20, 1367–1376 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  33. 33.

    Hsin, J. P. & Manley, J. L. The RNA polymerase II CTD coordinates transcription and RNA processing. Genes Dev. 26, 2119–2137 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. 34.

    Jimeno-Gonzalez, S., Haaning, L. L., Malagon, F. & Jensen, T. H. The yeast 5′-3ʹ exonuclease Rat1p functions during transcription elongation by RNA polymerase II. Mol. Cell 37, 580–587 (2010).

    PubMed  Article  CAS  Google Scholar 

  35. 35.

    Hilleren, P., McCarthy, T., Rosbash, M., Parker, R. & Jensen, T. H. Quality control of mRNA 3ʹ-end processing is linked to the nuclear exosome. Nature 413, 538–542 (2001).

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Milligan, L., Torchet, C., Allmang, C., Shipman, T. & Tollervey, D. A nuclear surveillance pathway for mRNAs with defective polyadenylation. Mol. Cell. Biol. 25, 9996–10004 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Torchet, C. et al. Processing of 3ʹ-extended read-through transcripts by the exosome can generate functional mRNAs. Mol. Cell 9, 1285–1296 (2002).

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Bousquet-Antonelli, C., Presutti, C. & Tollervey, D. Identification of a regulated pathway for nuclear pre-mRNA turnover. Cell 102, 765–775 (2000).

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Libri, D. et al. Interactions between mRNA export commitment, 3ʹ-end quality control, and nuclear degradation. Mol. Cell. Biol. 22, 8254–8266 (2002).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Rougemaille, M. et al. Dissecting mechanisms of nuclear mRNA surveillance in THO/sub2 complex mutants. EMBO J. 26, 2317–2326 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Vinciguerra, P., Iglesias, N., Camblong, J., Zenklusen, D. & Stutz, F. Perinuclear Mlp proteins downregulate gene expression in response to a defect in mRNA export. EMBO J. 24, 813–823 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Saguez, C. et al. Nuclear mRNA surveillance in THO/sub2 mutants is triggered by inefficient polyadenylation. Mol. Cell 31, 91–103 (2008).

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    Davidson, L., Kerr, A. & West, S. Co-transcriptional degradation of aberrant pre-mRNA by Xrn2. EMBO J. 31, 2566–2578 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44.

    Kim, M. et al. The yeast Rat1 exonuclease promotes transcription termination by RNA polymerase II. Nature 432, 517–522 (2004).

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    West, S., Gromak, N. & Proudfoot, N. J. Human 5′ 3′ exonuclease Xrn2 promotes transcription termination at co-transcriptional cleavage sites. Nature 432, 522–525 (2004).

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Eaton, J. D. et al. Xrn2 accelerates termination by RNA polymerase II, which is underpinned by CPSF73 activity. Genes Dev. 32, 127–139 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Porrua, O., Boudvillain, M. & Libri, D. Transcription termination: variations on common themes. Trends Genet. 32, 508–522 (2016).

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Lemay, J. F. et al. The RNA exosome promotes transcription termination of backtracked RNA polymerase II. Nat. Struct. Mol. Biol. 21, 919–926 (2014).

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Fong, N. et al. Effects of transcription elongation rate and Xrn2 exonuclease activity on RNA polymerase II termination suggest widespread kinetic competition. Mol. Cell 60, 256–267 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  50. 50.

    Das, B., Butler, J. S. & Sherman, F. Degradation of normal mRNA in the nucleus of Saccharomyces cerevisiae. Mol. Cell. Biol. 23, 5502–5515 (2003).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. 51.

    Schmid, M. et al. Rrp6p controls mRNA poly(A) tail length and its decoration with poly(A) binding proteins. Mol. Cell 47, 267–280 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  52. 52.

    Schmid, M. et al. The nuclear polyA-binding protein Nab2p is essential for mRNA production. Cell Rep. 12, 128–139 (2015).

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Grenier St-Sauveur, V., Soucek, S., Corbett, A. H. & Bachand, F. Poly(A) tail-mediated gene regulation by opposing roles of Nab2 and Pab2 nuclear poly(A)-binding proteins in pre-mRNA decay. Mol. Cell. Biol. 33, 4718–4731 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. 54.

    Soucek, S. et al. The evolutionarily-conserved polyadenosine RNA binding protein, Nab2, cooperates with splicing machinery to regulate the fate of pre-mRNA. Mol. Cell. Biol. 36, 2697–2714 (2016).

    PubMed Central  Article  CAS  Google Scholar 

  55. 55.

    Beaulieu, Y. B., Kleinman, C. L., Landry-Voyer, A. M., Majewski, J. & Bachand, F. Polyadenylation-dependent control of long noncoding RNA expression by the poly(A)-binding protein nuclear 1. PLoS Genet. 8, e1003078 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. 56.

    Bresson, S. M. & Conrad, N. K. The human nuclear poly(a)-binding protein promotes RNA hyperadenylation and decay. PLoS Genet. 9, e1003893 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Bresson, S. M., Hunter, O. V., Hunter, A. C. & Conrad, N. K. Canonical poly(A) polymerase activity promotes the decay of a wide variety of mammalian nuclear RNAs. PLoS Genet. 11, e1005610 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  58. 58.

    Eckmann, C. R., Rammelt, C. & Wahle, E. Control of poly(A) tail length. Wiley Interdiscip. Rev. RNA 2, 348–361 (2011).

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Libri, D. Nuclear poly(a)-binding proteins and nuclear degradation: take the mRNA and run? Mol. Cell 37, 3–5 (2010).

    PubMed  Article  CAS  Google Scholar 

  60. 60.

    Meola, N. & Jensen, T. H. Targeting the nuclear RNA exosome: poly(A) binding proteins enter the stage. RNA Biol. 14, 820–826 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Nguyen, D. et al. A polyadenylation-dependent 3′ end maturation pathway is required for the synthesis of the human telomerase RNA. Cell Rep. 13, 2244–2257 (2015).

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    da Rocha, S. T. & Heard, E. Novel players in X inactivation: insights into Xist-mediated gene silencing and chromosome conformation. Nat. Struct. Mol. Biol. 24, 197–204 (2017).

    PubMed  Article  CAS  Google Scholar 

  63. 63.

    Nakagawa, S. & Hirose, T. Paraspeckle nuclear bodies — useful uselessness? Cell. Mol. Life Sci. 69, 3027–3036 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    Coy, S., Volanakis, A., Shah, S. & Vasiljeva, L. The Sm complex is required for the processing of non-coding RNAs by the exosome. PLoS ONE 8, e65606 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  65. 65.

    Mitchell, P. Exosome substrate targeting: the long and short of it. Biochem. Soc. Trans. 42, 1129–1134 (2014).

    PubMed  Article  CAS  Google Scholar 

  66. 66.

    Brown, J. A., Valenstein, M. L., Yario, T. A., Tycowski, K. T. & Steitz, J. A. Formation of triple-helical structures by the 3ʹ-end sequences of MALAT1 and MENbeta noncoding RNAs. Proc. Natl Acad. Sci. USA 109, 19202–19207 (2012).

    PubMed  Article  Google Scholar 

  67. 67.

    Geisberg, J. V., Moqtaderi, Z., Fan, X., Ozsolak, F. & Struhl, K. Global analysis of mRNA isoform half-lives reveals stabilizing and destabilizing elements in yeast. Cell 156, 812–824 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Ogami, K. et al. An Mtr4/ZFC3H1 complex facilitates turnover of unstable nuclear RNAs to prevent their cytoplasmic transport and global translational repression. Genes Dev. 31, 1257–1271 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  69. 69.

    Fan, J. et al. Exosome cofactor hMTR4 competes with export adaptor ALYREF to ensure balanced nuclear RNA pools for degradation and export. EMBO J. 36, 2870–2886 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  70. 70.

    Shi, M. et al. ALYREF mainly binds to the 5′ and the 3′ regions of the mRNA in vivo. Nucleic Acids Res. 45, 9640–9653 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Richard, P. & Manley, J. L. R. Loops and links to human disease. J. Mol. Biol. 429, 3168–3180 (2017).

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Basu, U. et al. The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. Cell 144, 353–363 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    Pefanis, E. & Basu, U. RNA exosome regulates AID DNA mutator activity in the B cell genome. Adv. Immunol. 127, 257–308 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Pefanis, E. et al. Noncoding RNA transcription targets AID to divergently transcribed loci in B cells. Nature 514, 389–393 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  75. 75.

    Richard, P., Feng, S. & Manley, J. L. A. SUMO-dependent interaction between Senataxin and the exosome, disrupted in the neurodegenerative disease AOA2, targets the exosome to sites of transcription-induced DNA damage. Genes Dev. 27, 2227–2232 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Roth, K. M., Wolf, M. K., Rossi, M. & Butler, J. S. The nuclear exosome contributes to autogenous control of NAB2 mRNA levels. Mol. Cell. Biol. 25, 1577–1585 (2005).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Bresson, S., Tuck, A., Staneva, D. & Tollervey, D. Nuclear RNA decay pathways aid rapid remodeling of gene expression in yeast. Mol. Cell 65, 787–800.e5 (2017). This study reports differential binding of nuclear exosome co-factors Nab3 and Mtr4 during glucose starvation in S. cerevisiae, indicating a role for nuclear decay in reshaping the transcriptome.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    Chen, H. M., Futcher, B. & Leatherwood, J. The fission yeast RNA binding protein Mmi1 regulates meiotic genes by controlling intron specific splicing and polyadenylation coupled RNA turnover. PLoS ONE 6, e26804 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. 79.

    Harigaya, Y. et al. Selective elimination of messenger RNA prevents an incidence of untimely meiosis. Nature 442, 45–50 (2006). This paper describes how S. pombe meiosis-specific RNAs are degraded during vegetative growth by a pathway using the RNA-binding protein Mmi1 and the nuclear RNA exosome.

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Egan, E. D., Braun, C. R., Gygi, S. P. & Moazed, D. Post-transcriptional regulation of meiotic genes by a nuclear RNA silencing complex. RNA 20, 867–881 (2014).

    PubMed  CAS  Google Scholar 

  81. 81.

    Lee, N. N. et al. Mtr4-like protein coordinates nuclear RNA processing for heterochromatin assembly and for telomere maintenance. Cell 155, 1061–1074 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  82. 82.

    Zhou, Y. et al. The fission yeast MTREC complex targets CUTs and unspliced pre-mRNAs to the nuclear exosome. Nat. Commun. 6, 7050 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Yamanaka, S. et al. RNAi triggered by specialized machinery silences developmental genes and retrotransposons. Nature 493, 557–560 (2013).

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Tucker, J. F. et al. A novel epigenetic silencing pathway involving the highly conserved 5′–3′ exoribonuclease Dhp1/Rat1/Xrn2 in Schizosaccharomyces pombe. PLoS Genet. 12, e1005873 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  85. 85.

    Bergeron, D., Pal, G., Beaulieu, Y. B., Chabot, B. & Bachand, F. Regulated intron retention and nuclear pre-mRNA decay contribute to PABPN1 autoregulation. Mol. Cell. Biol. 35, 2503–2517 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Haimovich, G. et al. Gene expression is circular: factors for mRNA degradation also foster mRNA synthesis. Cell 153, 1000–1011 (2013).

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Sun, M. et al. Global analysis of eukaryotic mRNA degradation reveals Xrn1-dependent buffering of transcript levels. Mol. Cell 52, 52–62 (2013).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Sun, M. et al. Comparative dynamic transcriptome analysis (cDTA) reveals mutual feedback between mRNA synthesis and degradation. Genome Res. 22, 1350–1359 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Morton, D. J. et al. The RNA exosome and RNA exosome-linked disease. RNA 24, 127–142 (2018).

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Giunta, M. et al. Altered RNA metabolism due to a homozygous RBM7 mutation in a patient with spinal motor neuropathy. Hum. Mol. Genet. 25, 2985–2996 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  91. 91.

    Pak, C. et al. Mutation of the conserved polyadenosine RNA binding protein, ZC3H14/dNab2, impairs neural function in Drosophila and humans. Proc. Natl Acad. Sci. USA 108, 12390–12395 (2011).

    PubMed  Article  Google Scholar 

  92. 92.

    Brais, B. et al. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Nat. Genet. 18, 164–167 (1998).

    PubMed  Article  CAS  Google Scholar 

  93. 93.

    Robinson, S. R., Oliver, A. W., Chevassut, T. J. & Newbury, S. F. The 3ʹ to 5′ exoribonuclease DIS3: from structure and mechanisms to biological functions and role in human disease. Biomolecules 5, 1515–1539 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  94. 94.

    Rialdi, A. et al. The RNA exosome syncs IAV-RNAPII transcription to promote viral ribogenesis and infectivity. Cell 169, 679–692.e14 (2017). This study shows that virus RNA polymerase interacts with the RNA exosome and uses exosome decay fragments to prime viral transcription.

    PubMed  Article  CAS  Google Scholar 

  95. 95.

    Molleston, J. M. et al. A conserved virus-induced cytoplasmic TRAMP-like complex recruits the exosome to target viral RNA for degradation. Genes Dev. 30, 1658–1670 (2016).

  96. 96.

    Blasius, M., Wagner, S. A., Choudhary, C., Bartek, J. & Jackson, S. P. A quantitative 14-3-3 interaction screen connects the nuclear exosome targeting complex to the DNA damage response. Genes Dev. 28, 1977–1982 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

    Tiedje, C. et al. p38MAPK/MK2-mediated phosphorylation of RBM7 regulates the human nuclear exosome targeting complex. RNA 21, 262–278 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Zinder, J. C. & Lima, C. D. Targeting RNA for processing or destruction by the eukaryotic RNA exosome and its cofactors. Genes Dev. 31, 88–100 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. 99.

    Tudek, A. et al. Molecular basis for coordinating transcription termination with noncoding RNA degradation. Mol. Cell 55, 467–481 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  100. 100.

    Kim, K., Heo, D. H., Kim, I., Suh, J. Y. & Kim, M. Exosome cofactors connect transcription termination to RNA processing by guiding terminated transcripts to the appropriate exonuclease within the nuclear exosome. J. Biol. Chem. 291, 13229–13242 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. 101.

    Fasken, M. B., Laribee, R. N. & Corbett, A. H. Nab3 facilitates the function of the TRAMP complex in RNA processing via recruitment of Rrp6 independent of Nrd1. PLoS Genet. 11, e1005044 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    LaCava, J. et al. RNA degradation by the exosome is promoted by a nuclear polyadenylation complex. Cell 121, 713–724 (2005).

    PubMed  Article  CAS  Google Scholar 

  103. 103.

    Tomecki, R. et al. The human core exosome interacts with differentially localized processive RNases: hDIS3 and hDIS3L. EMBO J. 29, 2342–2357 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. 104.

    Turowski, T. W. & Tollervey, D. Cotranscriptional events in eukaryotic ribosome synthesis. Wiley Interdiscip. Rev. RNA 6, 129–139 (2015).

    PubMed  Article  CAS  Google Scholar 

  105. 105.

    Luo, W., Johnson, A. W. & Bentley, D. L. The role of Rat1 in coupling mRNA 3ʹ-end processing to transcription termination: implications for a unified allosteric-torpedo model. Genes Dev. 20, 954–965 (2006).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. 106.

    Stevens, A. & Maupin, M. K. A. 5′→3′ exoribonuclease of human placental nuclei: purification and substrate specificity. Nucleic Acids Res. 15, 695–708 (1987).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  107. 107.

    Stevens, A. & Maupin, M. K. A. 5′→3′ exoribonuclease of Saccharomyces cerevisiae: size and novel substrate specificity. Arch. Biochem. Biophys. 252, 339–347 (1987).

    PubMed  Article  CAS  Google Scholar 

  108. 108.

    Jiao, X. et al. Identification of a quality-control mechanism for mRNA 5′–end capping. Nature 467, 608–611 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  109. 109.

    Xiang, S. et al. Structure and function of the 5′→3′ exoribonuclease Rat1 and its activating partner Rai1. Nature 458, 784–788 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Chang, J. H. et al. Dxo1 is a new type of eukaryotic enzyme with both decapping and 5′–3′ exoribonuclease activity. Nat. Struct. Mol. Biol. 19, 1011–1017 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  111. 111.

    Jiao, X., Chang, J. H., Kilic, T., Tong, L. & Kiledjian, M. A mammalian pre-mRNA 5′ end capping quality control mechanism and an unexpected link of capping to pre-mRNA processing. Mol. Cell 50, 104–115 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  112. 112.

    Wan, J. et al. Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration. Nat. Genet. 44, 704–708 (2012). An early report linking mutation in an RNA exosome core component to human disease.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Boczonadi, V. et al. EXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia. Nat. Commun. 5, 4287 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  114. 114.

    Di Donato, N. et al. Mutations in EXOSC2 are associated with a novel syndrome characterised by retinitis pigmentosa, progressive hearing loss, premature ageing, short stature, mild intellectual disability and distinctive gestalt. J. Med. Genet. 53, 419–425 (2016).

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgements

Work in the T.H.J. laboratory is supported by the Danish National Research Council, the Lundbeck and Novo Nordisk Foundations and the European Research Council (grant 339953).

Reviewer information

Nature Reviews Genetics thanks Stefan Bresson, Alain Jacquier and David Tollervey for their contribution to the peer review of this work.

Author information

Affiliations

Authors

Contributions

Both authors contributed to all aspects of the article: researching and discussing content, writing, and reviewing and editing the manuscript before submission.

Corresponding authors

Correspondence to Manfred Schmid or Torben Heick Jensen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

RNA exosome

A multisubunit protein complex harbouring 3ʹ−5ʹ exoribonucleolytic and endoribonucleolytic activities. The exosome is conserved in archaea and eukaryotic lineages (see also Boxes 1,2).

Transcription termination

The process whereby a transcribing RNA polymerase (RNAP) dissociates from its genome template.

Small nuclear RNAs

(snRNAs). Also termed U snRNAs due to their high uridine content, snRNAs are packaged with proteins into small nuclear ribonucleoprotein (snRNP) complexes and form part of the spliceosome complex (for example, U1, U2, U4, U5, U6, U11, U12, U4atac and U6atac snRNPs) or histone pre-mRNA processing complex (for example, U7 snRNP).

Small nucleolar RNAs

(snoRNAs). RNAs containing conserved H/ACA or C/D box motifs that are packaged with proteins into small nucleolar ribonucleoprotein (snoRNP) complexes that guide the pseudouridylation or methylation of ribosomal RNAs (rRNAs) and other RNAs. Despite their name, snoRNAs are not necessarily restricted to the nucleolus.

Cryptic unstable transcripts

(CUTs). Highly unstable short Saccharomyces cerevisiae RNAs that are often encoded upstream and antisense of protein-coding genes.

Small nuclear ribonucleoprotein

(snRNP). A particle consisting of a small nuclear RNA (snRNA) and its protein-binding partners.

Nuclear exosome targeting

(NEXT). This complex is a mammalian nuclear RNA exosome adaptor containing the MTR4, RBM7 and ZCCHC8 proteins. It is involved in targeting the exosome to short and non-sequence-specific RNAs.

Torpedo model

A model that suggests that transcription termination is caused by the nuclear 5ʹ−3ʹ exonuclease (Rat1 in Saccharomyces cerevisae; XRN2 in mammals) degrading the nascent RNA attached to RNA polymerase (RNAP) after an endonucleolytic cleavage event, akin to a torpedo chasing after a target.

Co-transcriptional cleavage sites

(CoTCs). Regions positioned downstream of annotated poly(A) sites that are subjected to endonucleolytic cleavage to facilitate transcription termination. CoTCs are poorly defined and the mechanisms underlying RNA cleavage remain to be uncovered.

Roadblock terminators

Genomic regions that cause ‘roadblock’ transcription termination, for example, when they are occupied by a tightly bound DNA-binding protein that prevents RNA polymerase (RNAP) from transcribing beyond this site.

Poly(A) RNA exosome targeting

(PAXT). Connection made up of a mammalian nuclear RNA exosome adaptor that contains the MTR4, ZFC3H1 and PABPN1 proteins and is involved in recruiting the exosome to polyadenylated RNAs.

Long non-coding RNAs

(lncRNAs). RNAs that are most often defined as non-protein-coding transcripts longer than 200 nucleotides.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Schmid, M., Jensen, T.H. Controlling nuclear RNA levels. Nat Rev Genet 19, 518–529 (2018). https://doi.org/10.1038/s41576-018-0013-2

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing