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A Chemical Genomic Screen in Saccharomyces cerevisiae Reveals a Role for Diphthamidation of Translation Elongation Factor 2 in Inhibition of Protein Synthesis by Sordarin ^,

Departamento de Microbiología y Genética, Instituto de Microbiología Bioquímica, CSIC and Universidad de Salamanca, Salamanca, Spain,¹ Centro de Biología Molecular Severo Ochoa, CSIC and Universidad Autónoma de Madrid, Madrid, Spain²

Received 13 December 2007/ Returned for modification 10 January 2008/ Accepted 9 February 2008

Sordarin and its derivatives are antifungal compounds of potential clinical interest. Despite the highly conserved nature of the fungal and mammalian protein synthesis machineries, sordarin is a selective inhibitor of protein synthesis in fungal organisms. In cells sensitive to sordarin, its mode of action is through preventing the release of translation elongation factor 2 (eEF2) during the translocation step, thus blocking protein synthesis. To further investigate the cellular components required for the effects of sordarin in fungal cells, we have used the haploid deletion collection of Saccharomyces cerevisiae to systematically identify genes whose deletion confers sensitivity or resistance to the compound. Our results indicate that genes in a number of cellular pathways previously unknown to play a role in sordarin response are involved in its growth effects on fungal cells and reveal a specific requirement for the diphthamidation pathway of cells in causing eEF2 to be sensitive to the effects of sordarin on protein synthesis. Our results underscore the importance of the powerful genomic tools developed in yeast (Saccharomyces cerevisiae) to more comprehensively understanding the cellular mechanisms involved in the response to therapeutic agents.

Published ahead of print on 19 February 2008.

Supplemental material for this article may be found at http://aac.asm.org/.

^# Present address: Centro de Investigación del Cáncer, CSIC and Universidad de Salamanca, Salamanca, Spain.