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Etude des mutants synthétiques létaux avec l'AICAR chez la levure et conservation chez l'Homme

Abstract : Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach that aims to directly target the cancer cells. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-Amino-4-ImidazoleCArboxamide Ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to specifically inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of two several histone modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4methylation), greatly enhanced AICAR inhibitory effects on growth. Our results point to AICAR causing a significant accumulation of G1 cells due to its impact on Cln3 subcellular localization, whilebre1 or set1 deletion impacts on the two other G1 cyclins, by affecting CLN1 and CLN2 expression .As a consequence, AICAR and bre1/set1 deletions jointly affect all three G1 cyclins, leading to a condition that is known to result in synthetic lethality. Most importantly, these chemo-genetic synthetic interactions were conserved in human HCT116 cells. Knock-down of RNF40, ASH2L orKMT2D induced a highly significant increased sensitivity to AICAR. As KMT2D is mutated at high frequency in a variety of cancers, this synthetic lethal interaction has an interesting therapeutic potential.
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  • HAL Id : tel-01895256, version 1



Delphine Albrecht. Etude des mutants synthétiques létaux avec l'AICAR chez la levure et conservation chez l'Homme. Génétique. Université de Bordeaux, 2016. Français. ⟨NNT : 2016BORD0134⟩. ⟨tel-01895256⟩



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