Skip to main content

Thank you for visiting 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.

Crosstalk between RNA metabolic pathways: an RNOMICS approach


Eukaryotic cells contain many different RNA species. Nuclear pre-mRNAs and cytoplasmic mRNAs carry genomic information to the protein synthesis machinery, whereas many stable RNA species have important functional roles. The mature, functional forms of these RNA species are generated by post-transcriptional processing, and evidence has been accumulating that there are functional links between the various processing pathways. This indicates that there are regulatory networks that coordinate different stages of RNA metabolism. This article describes the aims and results, to date, of the European RNOMICS project as an example of an integrated approach to investigate these links.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Interactions between proteins involved in different aspects of RNA metabolism.


  1. 1

    Fields, S. & Song, O. A novel genetic system to detect protein–protein interactions. Nature 340, 245–246 (1989).

    CAS  PubMed  Google Scholar 

  2. 2

    Fromont-Racine, M., Rain, J. -C. & Legrain, P. Towards a functional analysis of the yeast genome through exhaustive two-hybrid screens. Nature Genet. 16, 277–282 (1997).

    CAS  PubMed  Google Scholar 

  3. 3

    Fromont-Racine, M., Rain, J. -C. & Legrain, P. Building protein–protein networks by two-hybrid mating strategy. Methods Enzymol. 350, 513–524 (2002).

    CAS  PubMed  Google Scholar 

  4. 4

    Ito, T. et al. A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc. Natl Acad. Sci. USA 98, 4569–4574 (2001).

    CAS  PubMed  Google Scholar 

  5. 5

    Gavin, A. C. et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141–147 (2002).

    CAS  PubMed  Google Scholar 

  6. 6

    Gould, K. L., Ren, L., Feoktistova, A. S., Jennings, J. L. & Link, A. J. Tandem affinity purification and identification of protein complex components. Methods 33, 239–244 (2004).

    CAS  PubMed  Google Scholar 

  7. 7

    Bentley, D. The mRNA assembly line: transcription and processing machines in the same factory. Curr. Opin. Cell Biol. 14, 336–342 (2002).

    CAS  PubMed  Google Scholar 

  8. 8

    Calvo, O. & Manley, J. L. Strange bedfellows: polyadenylation factors at the promoter. Genes Dev. 17, 1321–1327 (2003).

    CAS  PubMed  Google Scholar 

  9. 9

    Proudfoot, N. New perspectives on connecting messenger RNA 3′ end formation to transcription. Curr. Opin. Cell Biol. 16, 272–278 (2004).

    CAS  PubMed  Google Scholar 

  10. 10

    Fromont-Racine, M. et al. Genome-wide protein interaction screens reveal functional networks involving Sm-like proteins. Yeast 17, 95–110 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Bouveret, E., Rigaut, G., Shevchenko, A., Wilm, M. & Séraphin, B. An Sm-like protein complex that participates in mRNA degradation. EMBO J. 19, 1661–1671 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    He, W. & Parker, R. Functions of Lsm proteins in mRNA degradation and splicing. Curr. Opin. Cell Biol. 12, 346–350 (2000).

    CAS  PubMed  Google Scholar 

  13. 13

    Pannone, B. K. & Wolin, S. L. Sm-like proteins wRING the neck of mRNA. Curr. Biol. 10, R478–R481 (2000).

  14. 14

    Kambach, C., Walke, S. & Nagai, K. Structure and assembly of the spliceosomal small nuclear ribonucleoprotein particles. Curr. Opin. Struct. Biol. 9, 222–230 (1999).

    CAS  PubMed  Google Scholar 

  15. 15

    Fernandez, C. F., Pannone, B. K., Chen, X., Fuchs, G. & Wolin, S. L. An Lsm2–Lsm7 complex in Saccharomyces cerevisiae associates with the small nucleolar RNA snR5. Mol. Biol. Cell 15, 2842–2852 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Beggs, J. D. RNA processing and the Lsm proteins. Novartis Medal Lecture. Biochem. Soc. Trans. 33, 433–438 (2005).

    CAS  PubMed  Google Scholar 

  17. 17

    Mayes, A. E., Verdone, L., Legrain, P. & Beggs, J. D. Characterization of Sm-like proteins in yeast and their association with U6 snRNA. EMBO J. 18, 4321–4331 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Vidal, V. P., Verdone, L., Mayes, A. E. & Beggs, J. D. Characterization of U6 snRNA–protein interactions. RNA 5, 1470–1481 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Achsel, T. et al. A doughnut-shaped heteromer of human Sm-like proteins binds to the 3′-end of U6 snRNA, thereby facilitating U4/U6 duplex formation in vitro. EMBO J. 18, 5789–5802 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20

    Verdone, L., Galardi, S., Page, D. & Beggs, J. D. Lsm proteins promote regeneration of pre-mRNA splicing activity. Curr. Biol. 14, 1487–1491 (2004).

    CAS  PubMed  Google Scholar 

  21. 21

    Kufel, J., Allmang, C., Verdone, L., Beggs, J. D. & Tollervey, D. Lsm proteins are required for normal processing of pre-tRNAs and their efficient association with La-homologous protein Lhp1p. Mol. Cell. Biol. 22, 5248–5256 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Kufel, J., Allmang, C., Verdone, L., Beggs, J. & Tollervey, D. A complex pathway for 3′ processing of the yeast U3 snoRNA. Nucleic Acids Res. 31, 6788–6797 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Kufel, J., Allmang, C., Petfalski, E., Beggs, J. & Tollervey, D. Lsm proteins are required for normal processing and stability of ribosomal RNAs. J. Biol. Chem. 278, 2147–2156 (2003).

    CAS  PubMed  Google Scholar 

  24. 24

    Kufel, J., Bousquet-Antonelli, C., Beggs, J. D. & Tollervey, D. Nuclear pre-mRNA decapping and 5′ degradation in yeast require the Lsm2–8p complex. Mol. Cell. Biol. 24, 9646–9657 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Tharun, S. et al. Yeast Sm-like proteins function in mRNA decapping and decay. Nature 404, 515–518 (2000).

    CAS  PubMed  Google Scholar 

  26. 26

    Mitchell, P. & Tollervey, D. An NMD pathway in yeast involving accelerated deadenylation and exosome-mediated 3′→5′ degradation. Mol. Cell 11, 1405–1413 (2003).

    CAS  PubMed  Google Scholar 

  27. 27

    Cao, D. & Parker, R. Computational modeling and experimental analysis of nonsense-mediated decay in yeast. Cell 113, 533–545 (2003).

    CAS  PubMed  Google Scholar 

  28. 28

    Takahashi, S., Araki, Y., Sakuno, T. & Katada, T. Interaction between Ski7p and Upf1p is required for nonsense-mediated 3′–5′ mRNA decay in yeast. EMBO J. 22, 3951–3959 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Hilleren, P. & Parker, R. Mechanisms of mRNA surveillance in eukaryotes. Annu. Rev. Genet. 33, 229–260 (1999).

    CAS  PubMed  Google Scholar 

  30. 30

    Kshirsagar, M. & Parker, R. Identification of Edc3p as an enhancer of mRNA decapping in Saccharomyces cerevisiae. Genetics 166, 729–739 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Badis, G., Saveanu, C., Fromont-Racine, M. & Jacquier, A. Targeted mRNA degradation by deadenylation-independent decapping. Mol. Cell 15, 5–15 (2004).

    CAS  PubMed  Google Scholar 

  32. 32

    Kadaba, S. et al. Nuclear surveillance and degradation of hypomodified initiator tRNAMet in S. cerevisiae. Genes Dev. 18, 1227–1240 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Kuai, L., Fang, F., Butler, J. S. & Sherman, F. Polyadenylation of rRNA in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 101, 8581–8586 (2004).

    CAS  PubMed  Google Scholar 

  34. 34

    Allmang, C. et al. Functions of the exosome in rRNA, snoRNA and snRNA synthesis. EMBO J. 18, 5399–5410 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Van, H. A., Lennertz, P. & Parker, R. Yeast exosome mutants accumulate 3′-extended polyadenylated forms of U4 small nuclear RNA and small nucleolar RNAs. Mol. Cell. Biol. 20, 441–452 (2000).

    Google Scholar 

  36. 36

    Krogan, N. J. et al. High-definition macromolecular composition of yeast RNA-processing complexes. Mol. Cell 13, 225–239 (2004).

    CAS  PubMed  Google Scholar 

  37. 37

    Dreyfus, M. & Regnier, P. The poly(A) tail of mRNAs: bodyguard in eukaryotes, scavenger in bacteria. Cell 111, 611–613 (2002).

    CAS  PubMed  Google Scholar 

  38. 38

    Peng, W. T. et al. A panoramic view of yeast noncoding RNA processing. Cell 113, 919–933 (2003).

    CAS  PubMed  Google Scholar 

  39. 39

    Wu, L. F. et al. Large-scale prediction of Saccharomyces cerevisiae gene function using overlapping transcriptional clusters. Nature Genet. 31, 255–265 (2002).

    CAS  PubMed  Google Scholar 

  40. 40

    Wade, C., Shea, K. A., Jensen, R. V. & McAlear, M. A. EBP2 is a member of the yeast RRB regulon, a transcriptionally coregulated set of genes that are required for ribosome and rRNA biosynthesis. Mol. Cell. Biol. 21, 8638–8650 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Jorgensen, P. et al. A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. Genes Dev. 18, 2491–2505 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Tschochner, H. & Hurt, E. Pre-ribosomes on the road from the nucleolus to the cytoplasm. Trends Cell Biol. 13, 255–263 (2003).

    CAS  PubMed  Google Scholar 

  43. 43

    Saveanu, C. et al. Sequential protein association with nascent 60S ribosomal particles. Mol. Cell. Biol. 23, 4449–4460 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Granneman, S. & Baserga, S. J. Ribosome biogenesis: of knobs and RNA processing. Exp. Cell Res. 296, 43–50 (2004).

    CAS  PubMed  Google Scholar 

  45. 45

    Dez, C. & Tollervey, D. Ribosome synthesis meets the cell cycle. Curr. Opin. Microbiol. 7, 631–637 (2004).

    CAS  PubMed  Google Scholar 

  46. 46

    Saveanu, C. et al. Nog2p, a putative GTPase associated with pre-60S subunits and required for late 60S maturation steps. EMBO J. 20, 6475–6484 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Bassler, J. et al. Identification of a 60S preribosomal particle that is closely linked to nuclear export. Mol. Cell 8, 517–529 (2001).

    CAS  PubMed  Google Scholar 

  48. 48

    Bentley, D. Coupling RNA polymerase II transcription with pre-mRNA processing. Curr. Opin. Cell Biol. 11, 347–351 (1999).

    CAS  PubMed  Google Scholar 

  49. 49

    Hirose, Y. & Manley, J. L. RNA polymerase II and the integration of nuclear events. Genes Dev. 14, 1415–1429 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    Fatica, A., Dlakic, M. & Tollervey, D. Naf1 p is a box H/ACA snoRNP assembly factor. RNA 8, 1502–1514 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Dez, C., Noaillac-Depeyre, J., Caizergues-Ferrer, M. & Henry, Y. Naf1p, an essential nucleoplasmic factor specifically required for accumulation of box H/ACA small nucleolar RNPs. Mol. Cell. Biol. 22, 7053–7065 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52

    Yang, P. K., Rotondo, G., Legrain, P. & Chanfreau, G. The Shq1p–Naf1p complex is required for box H/ACA small nucleolar ribonucleoprotein particle biogenesis. J. Biol. Chem. 277, 45235–45242 (2002).

    CAS  PubMed  Google Scholar 

  53. 53

    Barilla, D., Lee, B. A. & Proudfoot, N. J. Cleavage/polyadenylation factor IA associates with the carboxyl-terminal domain of RNA polymerase II in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 98, 445–450 (2001).

    CAS  PubMed  Google Scholar 

  54. 54

    Dichtl, B. et al. A role for SSU72 in balancing RNA polymerase II transcription elongation and termination. Mol. Cell 10, 1139–1150 (2002).

    CAS  PubMed  Google Scholar 

  55. 55

    Dichtl, B. et al. Yhh1p/Cft1p directly links poly(A) site recognition and RNA polymerase II transcription termination. EMBO J. 21, 4125–4135 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Licatalosi, D. D. et al. Functional interaction of yeast pre-mRNA 3′ end processing factors with RNA polymerase II. Mol. Cell 9, 1101–1111 (2002).

    CAS  PubMed  Google Scholar 

  57. 57

    Skaar, D. A. & Greenleaf, A. L. The RNA polymerase II CTD kinase CTDK-I affects pre-mRNA 3′ cleavage/polyadenylation through the processing component Pti1p. Mol. Cell 10, 1429–1439 (2002).

    CAS  PubMed  Google Scholar 

  58. 58

    Zorio, D. A. R. & Bentley, D. L. The link between mRNA processing and transcription: communication works both ways. Exp. Cell Res. 296, 91–97 (2004).

    CAS  PubMed  Google Scholar 

  59. 59

    Sadowski, M., Dichtl, B., Hubner, W. & Keller, W. Independent functions of yeast Pcf11p in pre-mRNA 3′ end processing and in transcription termination. EMBO J. 22, 2167–2177 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

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

    CAS  PubMed  Google Scholar 

  61. 61

    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).

    CAS  PubMed  Google Scholar 

  62. 62

    Kyburz, A., Sadowski, M., Dichtl, B. & Keller, W. The role of the yeast cleavage and polyadenylation factor subunit Ydh1p/Cft2p in pre-mRNA 3′-end formation. Nucleic Acids Res. 31, 3936–3945 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Ganem, C. et al. Ssu72 is a phosphatase essential for transcription termination of snoRNAs and specific mRNAs in yeast. EMBO J. 22, 1588–1598 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Krishnamurthy, S., He, X., Reyes-Reyes, M., Moore, C. & Hampsey, M. Ssu72 is an RNA polymerase II CTD phosphatase. Mol. Cell 14, 387–394 (2004).

    CAS  PubMed  Google Scholar 

  65. 65

    Gallagher, J. E. et al. RNA polymerase I transcription and pre-rRNA processing are linked by specific SSU processome components. Genes Dev. 18, 2506–2517 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Custodio, N. et al. In vivo recruitment of exon junction complex proteins to transcription sites in mammalian cell nuclei. RNA 10, 622–633 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Lelivelt, M. J. & Culbertson, M. R. Yeast Upf proteins required for RNA surveillance affect global expression of the yeast transcriptome. Mol. Cell. Biol. 19, 6710–6719 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    He, F. et al. Genome-wide analysis of mRNAs regulated by the nonsense-mediated and 5′ to 3′ mRNA decay pathways in yeast. Mol. Cell 12, 1439–1452 (2003).

    CAS  PubMed  Google Scholar 

  69. 69

    Grigull, J., Mnaimneh, S., Pootoolal, J., Robinson, M. D. & Hughes, T. R. Genome-wide analysis of mRNA stability using transcription inhibitors and microarrays reveals posttranscriptional control of ribosome biogenesis factors. Mol. Cell. Biol. 24, 5534–5547 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Hieronymus, H. & Silver, P. A. A systems view of mRNP biology. Genes Dev. 18, 2845–2860 (2004).

    CAS  PubMed  Google Scholar 

  71. 71

    Garcia-Martinez, J., Aranda, A. & Perez-Ortin, J. E. Genomic run-on evaluates transcription rates for all yeast genes and identifies gene regulatory mechanisms. Mol. Cell 15, 303–313 (2004).

    CAS  PubMed  Google Scholar 

  72. 72

    Kotovic, K. M., Lockshon, D., Boric, L. & Neugebauer, K. M. Cotranscriptional recruitment of the U1 snRNP to intron-containing genes in yeast. Mol. Cell. Biol. 23, 5768–5779 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Yu, M. C. et al. Arginine methyltransferase affects interactions and recruitment of mRNA processing and export factors. Genes Dev. 18, 2024–2035 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Shav-Tal, Y., Singer, R. H. & Darzacq, X. Imaging gene expression in single living cells. Nature Rev. Mol. Cell Biol. 5, 855–862 (2004).

    CAS  Google Scholar 

  75. 75

    Damelin, M. & Silver, P. A. In situ analysis of spatial relationships between proteins of the nuclear pore complex. Biophys. J. 83, 3626–3636 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

    Sheff, M. A. & Thorn, K. S. Optimized cassettes for fluorescent protein tagging in Saccharomyces cerevisiae. Yeast 21, 661–670 (2004).

    CAS  PubMed  Google Scholar 

  77. 77

    Dix, I., Russell, C. S., Ben-Yehuda, S., Kupiec, M. & Beggs, J. D. The identification and characterization of a novel splicing protein, Isy1p, of Saccharomyces cerevisiae. RNA 5, 360–368 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

    Ben-Yehuda, S. et al. Genetic and physical interactions between factors involved in both cell cycle progression and pre-mRNA splicing in Saccharomyces cerevisiae. Genetics 156, 1503–1517 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Albers, M., Diment, A., Muraru, M., Russell, C. S. & Beggs, J. D. Identification and characterization of Prp45p and Prp46p, essential pre-mRNA splicing factors. RNA 9, 138–150 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Pan, X. et al. A robust toolkit for functional profiling of the yeast genome. Mol. Cell 16, 487–496 (2004).

    CAS  PubMed  Google Scholar 

  81. 81

    Clark, T. A., Sugnet, C. W. & Ares, M. Jr. Genomewide analysis of mRNA processing in yeast using splicing-specific microarrays. Science 296, 907–910 (2002).

    CAS  PubMed  Google Scholar 

  82. 82

    Braga, J., Desterro, J. M. & Carmo-Fonseca, M. Intracellular macromolecular mobility measured by fluorescence recovery after photobleaching with confocal laser scanning microscopes. Mol. Biol. Cell 15, 4749–4760 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


Research in the Beggs and Tollervey laboratories is mainly funded by grants from the Wellcome Trust and by an EC grant for the RNOMICS project.

Author information



Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links


Saccharomyces Genome Database






















Hybrigenics SA


Biomolecular Interaction Network Database

Database of Interacting Proteins


MINT — a Molecular Interactions database

Yeast GRID



HUPO Proteomics Standards Initiative



Davidson College course notes on FRAP

Molecular Probes Invitrogen detection systems

Becker & Hickl GmbH Lifetime Imaging Techniques for Optical Microscopy



Fluorescence lifetime measurements can yield information on the molecular microenvironment of a fluorescent molecule. Factors such as the binding to macromolecules and the proximity of molecules that can deplete the excited state by FRET can all modify the lifetime of a fluorophore (see Becker & Hickl GmbH Lifetime Imaging Techniques for Optical Microscopy).


A microscope technique used to measure the movement (for example, diffusion rates) of fluorescently tagged molecules over time in vivo. Specific regions in a cell are irreversibly photobleached using a laser; fluorescence is restored by diffusion of fluorescently tagged unbleached molecules into the bleached area (see Davidson College, Molecular Biology course notes on FRAP).


The non-radiative transfer of energy from a donor fluorophore to an acceptor fluorophore that is typically <80 Å away. FRET will only occur between fluorophores in which the emission spectrum of the donor has a significant overlap with the excitation of the acceptor. FRET can be used to detect the co-localization of proteins and other molecules with spatial resolution beyond the limits of conventional optical microscopy (see Molecular Probes Invitrogen detection systems).


When two yeast mutations are viable individually, but die when combined, they are described as being synthetic lethal. This genetic interaction indicates a functional relationship, either because they affect alternative pathways for a process, or because the gene products might be components of the same pathway or even of the same complex and the defects caused by the mutations are additive. Screening for mutations that are synthetic lethal with a mutation in a factor of interest might identify functionally related factors.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Beggs, J., Tollervey, D. Crosstalk between RNA metabolic pathways: an RNOMICS approach. Nat Rev Mol Cell Biol 6, 423–429 (2005).

Download citation

Further reading


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