Skip to Main content Skip to Navigation
Theses

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.
Document type :
Theses
Complete list of metadatas

Cited literature [180 references]  Display  Hide  Download

https://tel.archives-ouvertes.fr/tel-01895256
Contributor : Abes Star :  Contact
Submitted on : Monday, October 15, 2018 - 1:01:18 AM
Last modification on : Thursday, September 3, 2020 - 4:55:21 AM
Long-term archiving on: : Wednesday, January 16, 2019 - 1:17:22 PM

File

ALBRECHT_DELPHINE_2016.pdf
Version validated by the jury (STAR)

Identifiers

  • HAL Id : tel-01895256, version 1

Collections

Citation

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⟩

Share

Metrics

Record views

221

Files downloads

210