Synthetic Lethality between Gene Defects Affecting a Single Non-essential Molecular Pathway with Reversible Steps
Figure 6
Modeling possible scenarios of single and double synthetic lethal mutations.
Pathway steady states depicted as Normal states (N) as Normal Robust (NR) and Normal Fragile (NF); Mutant states (M) as compensated state dependent on compensatory pathway EC(C); death from DNA damage (DD) and death from toxicity (DT). Dynamic plots show prediction of model for evolution of substrate (S), intermediate (I) and product (P) amounts over time corresponding to the choice of kinetic parameters shown on the Model diagram. (X-axis)-time, (Y-axis)-substances level. F1, F2, R1, R2, and EC refer to the enzymes catalyzing the two forward and two backward reactions as well as the compensatory pathway, respectively (see Figure 3). (↓)-complete knock-down or mutational loss of function; (↑)-over-expression. A deletion mutant was simulated by setting the corresponding kinetic rate constant to zero. An overexpression mutant was simulated by setting the corresponding kinetic rate constant sufficiently high to have a qualitative effect onto the steady state or the dynamics in the simulations. Some double mutants are not shown due to their triviality (such as F1↓F2↓) or difficulties with interpretation (such as F1↓R1↓). For more modeling scenarios see Figure S5 in Text S1.