title: Synthetic lethality between gene defects affecting a single non-essential molecular pathway with reversible steps.
abstract: Systematic analysis of synthetic lethality (SL) constitutes a critical tool for systems biology to decipher molecular pathways. The most accepted mechanistic explanation of SL is that the two genes function in parallel, mutually compensatory pathways, known as between-pathway SL. However, recent genome-wide analyses in yeast identified a significant number of within-pathway negative genetic interactions. The molecular mechanisms leading to within-pathway SL are not fully understood. Here, we propose a novel mechanism leading to within-pathway SL involving two genes functioning in a single non-essential pathway. This type of SL termed within-reversible-pathway SL involves reversible pathway steps, catalyzed by different enzymes in the forward and backward directions, and kinetic trapping of a potentially toxic intermediate. Experimental data with recombinational DNA repair genes validate the concept. Mathematical modeling recapitulates the possibility of kinetic trapping and revealed the potential contributions of synthetic, dosage-lethal interactions in such a genetic system as well as the possibility of within-pathway positive masking interactions. Analysis of yeast gene interaction and pathway data suggests broad applicability of this novel concept. These observations extend the canonical interpretation of synthetic-lethal or synthetic-sick interactions with direct implications to reconstruct molecular pathways and improve therapeutic approaches to diseases such as cancer.
authors.affiliation: Institut Curie, Paris, France. Andrei.Zinovyev@curie.fr
authors.forename: Andrei
authors.initials: A
authors.lastname: Zinovyev
authors.forename: Inna
authors.initials: I
authors.lastname: Kuperstein
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Barillot
authors.forename: Wolf-Dietrich
authors.initials: WD
authors.lastname: Heyer
mesh_terms: D000465:Algorithms; D000818:Animals; D002384:Catalysis; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D004331:Drosophila melanogaster; D004798:Enzymes / Q000737:chemistry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D011995:Recombination, Genetic
chemical_list: D004798:Enzymes; D004247:DNA