Synthetic Lethality between Gene Defects Affecting a Single Non-essential Molecular Pathway with Reversible Steps
Figure 8
Examples of molecular processes with alternative pathways and potential to kinetic trap.
A) Multiple post-translational protein modifications (phosphorylation followed by ubiquitination; acetylation followed by phosphorylation; sumotargeted ubiquitination, etc.). M1 and M2 represent two types of post-translational modifications. MOD1–4 represent enzymes catalyzing the reactions. Kinetic trapping of an intermediate modification can drastically disturb the balance between signaling pathways (e.g. #23 in Figure 2) B) Protein folding control by chaperones. Protein folding is controlled by chaperones (#18 in Figure 2) and may generate partially unfolded proteins as toxic intermediates which are subject to degradation [55]. Regulation of protein folding homeostasis is essential for protein pool control [56]; C) Lack of balance between production and detoxification of ROS leads to significant increases or drop in ROS levels that can be detrimental for cell signaling [57]–[59] (#19 in Figure 2). D) Coordinated sumoylation-desumoylation is important for proper signal propagation [60]–[62]. E) Glycan biosynthesis and protein glycosylation depend on the availability of common carrier dolichol phosphate (P-DOL). Correct recycling of P-DOL is important for sustaining the pool and utilization of this carrier in other glycans biosynthesis pathways. Kinetic trapping can consume the pool of P-DOL and perturb cell signaling [63], [64] (#2, 3 and 26 in Figure 2) F) Protein ubiquitylation is not only a tagging signal for degradation, but also involved in signaling. The correct tuning between two functions of ubiquitylation depends on the type and the length of ubiquitin (UB) polymer transferred to the protein and at the ubiquitylation site [65]. Monoubiquitylated proteins participate in signal transduction [66], [67], whereas K48-polyubiquitylated proteins are redirected to the proteasome for proteolysis. Thus, the balance between protein homeostasis and ubiquitin-dependent signaling is essential [68].