Synthetic rescue (or synthetic recovery or synthetic viability when a lethal

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...

is rescued ) refers to a genetic interaction in which a cell that is nonviable, sensitive to a specific drug, or otherwise impaired due to the presence of a

genetic mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...

becomes viable when the original mutation is combined with a second mutation in a different gene. The second mutation can either be a loss-of-function mutation (equivalent to a knockout) or a

gain-of-function mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...

. Synthetic rescue could potentially be exploited for

gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...

, but it also provides information on the function of the genes involved in the interaction.

Types of genetic suppression

Dosage-mediated suppression

Dosage-mediated suppression occurs when the suppression of the mutant phenotype is mediated by the over expression of a second suppressor gene. This can occur when the initial mutations destabilize a protein-protein interaction and over expression of the interacting protein bypass the negative effect of the initial mutation.

Interaction-mediated suppression

Interaction-mediated suppression occurs when a deleterious mutation in a component of a protein complex destabilizes the complex. A compensatory mutation in another component of the protein complex can then suppress the deleterious phenotype by re-establishing the interaction between the two proteins. It usually means that the deleterious mutation and the suppressive mutation occurs in two residues that are closely located in the tridimensional structure of the multi-protein complex. As thus, this kind of suppression provides indirect information on the molecular structure of the proteins involved.

Experimental observation of theoretical prediction

The strongest form of synthetic rescues, in which the deleterious impact of a gene knockout is mitigated by an additional genetic perturbation that is also deleterious when considered in isolation, was modeled and predicted theoretically for gene interactions mediated by the metabolic network. This strong form of synthetic rescue has been recently observed in experiments in both ''

Saccharomyces cerevisiae ''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have been o ...

''. and ''

Escherichia coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...

''. Patient survival analysis was also shown to predict synthetic rescues and other types of interactions.

tRNA-mediated suppression

Genetic suppression can be mediated by

tRNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...

genes when a mutation alters their anticodon sequence. For example, a tRNA designated for the recognition of the codon TCA and the corresponding insertion of

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...

in the growing polypeptide chain can mutate so that it recognize a TAA stop codon and promote the insertion of serine instead of the termination of the polypeptide chain. This could be particularly useful when a nonsense mutation (TCA >TAA) prevents the expression of a gene by either leading to a partially completed polypeptide or degradation of the

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

nonsense-mediated decay Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant ...

. The redundancy of tRNA genes makes sure that such mutation would not prevent the normal insertion of serines when the TCA codon specifies them.

References