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Question: Synthetic lethality screen is a powerful genetic approach that is commonly used to find functional interacting partners. Please use an example, such as those in the paper, to describe what is synthetic lethality (how it works).

Answer 1

Synthetic lethality is thus defined as a type of genetic interaction where the co-occurrence of two genetic events results in organismal or cellular death .Similarly, genetic combinations that yield a non-lethal growth impairment are called synthetic sick but are usually grouped together with synthetic lethal interactions.Combinations of other types of perturbations can also result in synthetic lethality, including overexpression of genes, the action of a chemical compound or environmental change.Synthetic lethality is a cellular condition in which two non-essential, non-allelic genes, each dispensable for viability, have a lethal phenotype when co-depleted. Synthetic lethal screens are an essential component of a geneticist’s toolbox, serving as a starting point to identify gene products with similar or overlapping functions, and pathways with parallel or compensatory mechanisms.

Synthetic lethal genetic interactions exist because of the mechanisms employed by cells and organisms to maintain homeostasis in the face of diverse genetic and environmental challenges. This robustness of cells and organisms is thought to play a critical role in evolution, developmental canalization (i.e., the ability to produce the same phenotype regardless of genotype) and multifactorial diseases such as cancer.Synthetic lethality can be thought of as a feature of genetic robustness.Genetic robustness is established via various buffering mechanisms, such as functional redundancy and proteins known as capacitors. In diploid organisms, redundancy is the simplest type of buffering due to the presence of two alleles in the genome.

Several RNAi screening approaches were reported used to identify synthetic lethal interactions with oncogenic RAS, which is frequently mutated in a variety of cancers but difficult to target directly using small molecule inhibitors and therefore attractive for a synthetic lethal therapy. As well as being some of the most comprehensive human synthetic lethality screens to date, these studies also effectively highlight the different screening approaches that are currently available. In addition, they offer an opportunity to discuss some of the current limitations and challenges of synthetic lethality screens in human cells.

Synthetic lethality is a valuable concept to understand the functions of genes, the mechanism of action of drugs and their interactions, and has immediate relevance for cancer therapy. Synthetic lethality provides a framework for the mechanism of action of chemotherapy.