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Jamal Tazi

Research Focus

Our studies of pre-mRNA splicing are focused on how the splicing machinery manages to locate and pair 5' and 3' splice sites in a tissue-specific and developmentally regulated manner. We are using Drosophila as a model system to identify novel splicing factors and their cognate target genes. In this organism, we have characterised the structure and function of novel members of the serine arginine-rich (SR) protein family and determined how their activity is regulated by phosphorylation and/or by antagonistic factors. A large screen for suppressors of the phenotypes induced by SR protein over expression revealed an intriguing connection between splicing and translation.

In humans the complexity of constitutive and alternative splice site recognition suggests multiple levels of regulation, each resulting from a combination of cis-elements and trans-acting factors adapting the enzyme responsible for intron excision (the spliceosome) to various situations. The significance of these observations, especially in regard to human pathologies, is that there is a considerable number of disease-causing mutations in exons and introns that disrupt previously unrecognised auxiliary cis-elements as well as the well-known classical splice sites.

Also, viruses like the human immunodeficiency virus (HIV) uses a combination of several alternative splice sites to generate more than 40 different mRNAs from its single transcribed genome pre-mRNA that are essential for its life cycle. Thus, targeting either conserved constituent of the spliceosome and/or regulatory sequences or factors that bind to them, holds great promise for future therapeutic action to correct aberrant splicing caused by mutations or to prevent viral infection.

Our laboratory is currently developing an entirely new approach in which specific splicing factors are targeted by small chemical molecules. A large screen programme has been conducted with the chemical library of the Curie Institute. Several molecules were found to counter the splicing stimulatory effect of individual members of the SR protein family and have been selected for further development in pathological splicing.

Publications

  1. Ghigna, C., De Toledo, M., Bonomi, S., Valacca, C., Gallo, S., Apicella, M., Eperon, I., Tazi, J. and Biamonti, G. (2010). Pro-metastatic splicing of Ron proto-oncogene mRNA can be reversed: Therapeutic potential of bifunctional oligonucleotides and indole derivatives. RNA Biology 7(4), [Epub ahead of print].
  2. Baldin, V., Militello, M., Thomas, Y., Doucet, C., Fic, W., Boireau, S., Jariel-Encontre, I., Piechaczyk, M., Bertrand, E., Tazi, J., Coux, O. (2008). A Novel Role for PA28{gamma}-Proteasome in Nuclear Speckle Organization and SR Protein Trafficking. Molecular Biology of the Cell 19(4), 1706-16.
  3. Tournier, I., Vezain, M., Martins, A., Charbonnier, F., Baert-Desurmont, S., Olschwang, S., Q. Wang, Q., Buisine, M-P., Soret, J., Tazi, J., Frébourg, T., and Tosi, M. (2008). A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Human Mutation 2008 June 16. [epub ahead of print]
  4. Durand, S., Cougot, N., Mahuteau-Betzer, F., Nguyen, C.H., Grierson, D.S., Bertrand, E., Tazi, J., Lejeune, F. (2007). Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies. Journal of Cell Biology 178(7), 1145-60.
  5. Gabut, M., Dejardin, J., Tazi, J., Soret, J. (2007). The SR family proteins B52 and dASF/SF2 modulate development of the Drosophila visual system by regulating specific RNA targets. Molecular and Cellular Biology 27(8), 3087-97.
  6. Fic, W., Juge, F., Soret, J., Tazi, J. (2007). Eye development under the control of SRp55/B52-mediated alternative splicing of eyeless. PLoS One 2(2), e253.
  7. Bakkour, N., Lin, Y.L., Maire, S., Ayadi, L., Mahuteau-Betzer, F., Nguyen, C.H., Mettling, C., Portales, P., Grierson, D., Chabot, B., Jeanteur, P., Branlant, C., Corbeau, P., Tazi, J. (2007). Small-molecule inhibition of HIV pre-mRNA splicing as a novel antiretroviral therapy to overcome drug resistance. PLoS Pathogens 3(10), 1530-9.
  8. Soret, J., Gabut, M., and Tazi, J. (2006). SR proteins as potential targets for therapy. Progress in Molecular and Subcellular Biology (Invited review) 44, 65-87.
  9. Soret, J., Bakkour, N., Maire, S., Durand, S., Zekri, L., Gabut, M., Fic, W., Divita, G., Rivalle, C., Dauzonne, D., Nguyen, C.H., Jeanteur, Ph. and Tazi, J. (2005) Selective modification of alternative splicing by indole derivatives that target SR protein splicing factors. Proceedings of the National Academy of Sciences USA 102, 8764-8769.
  10. Tazi, J., Durand, S., Jeanteur, Ph. (2005) Spliceosome: a novel multi-facet target for therapy. Trends in Biochemical Sciences 30, 469-478.
  11. Gabut, M., Miné, M., Marsac, C., Brivet, M., Tazi, J. and Soret, J. (2005) The SR protein SC35 is responsible for aberrant splicing of the E1? Pyruvate Dehydrogenase mRNA in a case of mental retardation with lactic acidosis. Molecular and Cellular Biology 25, 3286-3294.
  12. Allemand, E., Gattoni, R., Stevenin, J., Bourbon, H-M., Caceres, J., Soret, J. and Tazi, J. (2001) Distinctive features of Drosophila SF2/ASF splicing factor RS domain: implication for specific phosphorylation, shuttling, and splicing activation. Molecular and Cellular Biology 21, 1345-1359.
  13. Labourier, E., Bourbon, H.M., Gallouzi, I., Fostier, M., Allemand, E. and Tazi, J. (1999) Antagonism between RSF1 and SR proteins for both splice-site recognition in vitro and Drosophila development. Genes and Development 13, 740-753.

Key lab techniques: biochemistry: RNA-protein interactions, in vitro splicing assays, protein purification, RNA purification and analysis.

Key lab reagents - library of small chemical molecules from the Institut Curie (Paris) in 96 well plates and synthesis of novel molecules; collections of ESE-dependent constructs with luciferase or GFP reporters to be used in cultured cells; Constructs for pathological splicing: SMN, Progeria and Leigh syndrome; Animal models - Drosophila over expressing GFP fused individual SR proteins under UAS driver, Drosophila lines with P element containing UAS sequences, mouse model for breast cancer, mouse model for leukaemia, mouse model for Muscular Dystrophy (mdx) which harbours a mutation in Dystrophin gene.

Lab contact: johann.soret@igmm.cnrs.fr; sophie.maire@igmm.cnrs.fr

Lab website: www.igmm.cnrs.fr