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Séminaire Chimie ED459

Molecular tools for probing the G4-genome

Dr. Marie-Paule Teulade-Fichou, D.R. CNRS (Conception Synthèse et Vectorisation de Biomolécules, UMR 176 CNRS, Institut Curie, Université Paris-Sud Orsay)

publié le , mis à jour le

Le Jeudi 11 décembre 2014 à 13h45
UM2, salle de cours SC-25.01

(la conférence sera préserntée en français)

For many years our research efforts have been focused on the design of small molecules for probing nucleic acid structures. Our targets are more specifically alternative secondary structures such as G-quadruplexes (G4) that can be found in G-rich regions. These structures are involved in various genomic dysfunctions and may ultimately cause genetic instability related to cancer development. [1] Our primary aim is to provide chemical biology tools for a better understanding of the roles of these structures. Our secondary aim is to evaluate the cancer therapeutic potential of quadruplex-targeted agents.

A large number of compounds have been developed for targeting quadruplexes but few display the criteria of selectivity required for in-cell probing. [2] We have contributed to develop the bisquinolinium series and in particular the PhenDC derivatives that rank amongst the best G4 probes usable in yeast and mammalian cells. [3] We will give a short overview of recent chemical developments of these agents and of their use for biological studies aiming at providing experimental evidence of quadruplex formation in vitro and in cells. [4-6]

References

1. N. Maizels, G4 motifs in human genes, Ann. N.Y. Acad. Sci. 2012, 1267, 53–60.
2. D. Monchaud et al, A hitchiker guide to G-quadruplex ligands, Org. Biomol. Chem. 2008, 6, 627–636
3. (a) De Cian et al, Highly efficient bisquinolinum compounds for quadruplex recognition, J. Am. Chem. Soc. 2007, 129, 1856. (b) W.J Chung et al., Solution structure of a G-quadruplex bound to the Bisquinolium compound PhenDC3, Angew. Chem. Int. Ed. 2014, 53, 999–1002.
4. (a) A. Piazza et al., Genetic instability triggered by G-quadruplex interacting Phen-DC compounds in Saccharomyces cerevisiae, Nucleic Acid Res. 2010, 38, 4337–4348. (b) J. Lopez et al. G-quadruplex-induced instability during leading strand replication, EMBO J. 2011, 30, 4033–4046.
5. S. Kumar Bharti, J. A. Sommers, J. Kuper, F. Hamon, K. Shin-ya, M.-P. Teulade-Fichou, C. Kisker, R. M. Brosh, Jr., Specialization among iron-sulfur cluster helicases to resolve G-quadruplex DNA structures that threaten genomic stability, J. Biol. Chem. 2013, 288, 28217–28229.
6. (a) D. Gomez, A. Guédin, J.-L. Mergny, B. Salles, J.-F. Riou, M.-P. Teulade Fichou, P. Calsou, A G-quadruplex structure within the 5’UTR of the TRF2 mRNA represses translation in human cells, Nucleic Acid Res. 2010, 38, 7187–7198. (b) K. Halder, E. Largy, M.-P. Teulade-Fichou, J. S. Hartig efficient suppression of gene expression by targeting 5’-UTR-based RNA quadruplexes with bisquinolinium compounds, ChemBioChem 2011, 12, 1663–1668.

Contact local IBMM : Prof. Michaël Smietana (dépt. DACAN)

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