Name
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. |
Year | DOI | Venue |
|---|---|---|
2013 | 10.1371/journal.pcbi.1003016 | PLOS COMPUTATIONAL BIOLOGY |
Keywords | Field | DocType |
dna repair,computer simulation,catalysis,algorithms,enzymes,computational biology,gene expression profiling,mutation,gene expression regulation,dna,gene regulatory networks | Gene,Biology,Systems biology,Regulation of gene expression,Synthetic lethality,Bioinformatics,DNA repair,Genetics,Gene regulatory network,Gene expression profiling,Mutation | Journal |
Volume | Issue | ISSN |
9 | 4 | 1553-7358 |
Citations | PageRank | References |
0 | 0.34 | 3 |
Authors | ||
4 | ||
Name | Order | Citations | PageRank |
|---|---|---|---|
| Andrei Zinovyev | 1 | 282 | 27.30 |
| Inna Kuperstein | 2 | 6 | 2.16 |
| Emmanuel Barillot | 3 | 950 | 165.00 |
| Wolf-Dietrich Heyer | 4 | 0 | 0.68 |