Synthetic Lethality between Gene Defects Affecting a Single Non-essential Molecular Pathway with Reversible Steps

INSERM, U900, Paris, France
PLoS Computational Biology (Impact Factor: 4.62). 04/2013; 9(4):e1003016. DOI: 10.1371/journal.pcbi.1003016
Source: PubMed


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.

Download full-text


Available from: Andrei Zinovyev, Jun 28, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Prediction tools are commonly used in pre-clinical research to assist target selection, to optimize drug potency or to predict the pharmacological profile of drug candidates. In silico prediction and overcoming drug resistance is a new opportunity that creates a high interest in pharmaceutical research. This review presents two main in silico strategies to meet this challenge: a structure-based approach to study the influence of mutations on the drug-target interaction and a system-biology approach to identify resistance pathways for a given drug. In silico screening of synergies between therapeutic and resistant pathways through biological network analysis is an example of technique to escape drug resistance. Structure-based drug design and in silico system biology are complementary approaches to reach few objectives at once: increase efficiency, reduce toxicity and overcoming drug resistance.
    No preview · Article · Mar 2014 · Drug Discovery Today Technologies
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer treatment decisions rely on genetics, large data screens and clinical pharmacology. Here we point out that genetic analysis and treatment decisions may overlook critical elements in cancer development, progression and drug resistance. Two critical structural elements are missing in genetics-based decision-making: the mechanisms of oncogenic mutations and the cellular network which is rewired in cancer. These lay the foundation for the structural basis for cancer treatment decisions, which is rooted in the physical principles of the molecular conformational behavior of single molecules and their interactions. Improved tumor mutational analysis platforms and knowledge of the redundant pathways which can take over in cancer, may not only supplement known actionable findings, but forecast possible cancer progression and resistance. Such forward-looking can be powerful, endowing the oncologist with mechanistic insight and cancer prognosis, and consequently more informed treatment options. Examples include redundant pathways taking over after inhibition of EGFR constitutive activation, mutations in PIK3CA p110α and p85, and the non-hotspot AKT1 mutants conferring constitutive membrane localization.
    Full-text · Article · Sep 2014 · Oncotarget
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The problem of dealing with complexity arises when we fail to achieve a desired behavior of biological systems (for example, in cancer treatment). In this review I formulate the problem of tackling biological complexity at the level of large-dimensional datasets and complex mathematical models of reaction networks. I show that in many cases the complexity can be reduced by using approximation by simpler objects (for example, using principal graphs for data dimension reduction, and using dominant systems for reducing complex models). Examples of dealing with complexity from various fields of molecular systems biology are used, in particular, from the analysis of cancer transcriptomes, mathematical modeling of protein synthesis and of cell fate decisions between death and life.
    Full-text · Article · Jun 2015 · Mathematical Modelling of Natural Phenomena
Show more