Figure 2.

Conceptual Models Depicting the Underlying Mechanisms that Account for Synthetic Lethal Interactions. Conceptual models detailing three mechanisms that produce a synthetic lethal interaction—circles represent genes, cancer-associated mutations, or deletions are identified by a red “X”, and synthetic lethal interactors (i.e., drug targets) are identified by blue arrows. (a) Partial ablation of two functions encoded within a single essential pathway (e.g., epistasis group), such that the pathway is no longer functional. (b) Ablation of two functions encoded within two distinct parallel pathways. For example, defects in DNA replication would lead to DNA errors requiring repair, and small molecule inhibitors preventing accurate repair will cause lethality. (c) Ablation of two functions encoded within two separate pathways that together impinge on a single essential process. For example, DNA double strand breaks can only be repaired through two pathways, namely homologous recombination repair and non-homologous end joining—defects and inhibition of both pathways will cause cellular cytotoxicity.