Synthetic lethality

Synthetic lethality is a genetic interaction where the combination of mutations in two or more genes leads to cell death, but a mutation in only one of these genes does not. The concept of synthetic lethality is used in cancer therapy to selectively kill cancer cells while sparing normal cells.

Overview

Synthetic lethality arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through mutations, epigenetic alterations or inhibitors of the genes. Synthetic lethality is synthetically viable if the combination of deficiencies does not result in cell death.

Synthetic lethality in cancer therapy

In cancer therapy, synthetic lethality is used to selectively kill cancer cells while sparing normal cells. This is achieved by exploiting the genetic differences between cancer cells and normal cells. For example, cancer cells often have mutations in DNA repair genes, making them more reliant on other DNA repair pathways. If these other pathways are inhibited, the cancer cells die, a phenomenon known as synthetic lethality.

Examples

One of the best-known examples of synthetic lethality in cancer therapy is the use of poly (ADP-ribose) polymerase (PARP) inhibitors in cancers with BRCA1 or BRCA2 mutations. BRCA1 and BRCA2 are involved in homologous recombination, a type of DNA repair. Mutations in these genes make cancer cells more reliant on other DNA repair pathways, such as the one involving PARP. Inhibiting PARP in these cells leads to synthetic lethality.

See also

• Genetic interaction
• Cancer therapy
• DNA repair
• PARP inhibitors
• BRCA1
• BRCA2

References

Synthetic lethality Resources
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