Synthetic lethality

Synthetic Lethality

Illustration of synthetic lethality in genetic pathways.

Synthetic lethality occurs when the combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes does not affect cell viability. This concept is particularly significant in the field of cancer research and genetic engineering, as it provides a strategy for targeting cancer cells while sparing normal cells.

Mechanism

Synthetic lethality arises when two genes interact in such a way that the loss of function of either gene alone is compatible with cell survival, but the simultaneous loss of both genes results in cell death. This can occur through various mechanisms, such as:

• Parallel Pathways: Two genes may function in parallel pathways that compensate for each other. If one pathway is disrupted, the other can still maintain essential cellular functions.
• Redundant Functions: Two genes may have overlapping functions, and the loss of both leads to a failure in essential cellular processes.
• Compensatory Mechanisms: One gene may compensate for the loss of another through upregulation or activation of alternative pathways.

Applications in Cancer Therapy

Synthetic lethality is exploited in cancer therapy to selectively target cancer cells. Cancer cells often harbor specific genetic mutations that make them reliant on certain pathways for survival. By identifying and targeting a synthetic lethal partner of a mutated gene in cancer cells, it is possible to induce cell death selectively in cancer cells while sparing normal cells.

PARP Inhibitors

One of the most well-known applications of synthetic lethality in cancer therapy is the use of PARP inhibitors in BRCA1 or BRCA2 mutated cancers. BRCA1 and BRCA2 are involved in DNA repair through homologous recombination. Inhibiting PARP, a protein involved in single-strand break repair, leads to the accumulation of DNA damage in BRCA-deficient cells, resulting in cell death.

Research and Development

Research into synthetic lethality involves identifying gene pairs that exhibit synthetic lethal interactions. This is often done using high-throughput screening techniques, such as CRISPR or RNA interference (RNAi) screens, to systematically knock out genes and observe the effects on cell viability.

Challenges and Future Directions

While synthetic lethality offers a promising approach to cancer therapy, there are challenges in its application:

• Identification of Synthetic Lethal Pairs: Discovering clinically relevant synthetic lethal interactions requires extensive research and validation.
• Resistance Mechanisms: Cancer cells may develop resistance to synthetic lethal therapies through various mechanisms, such as secondary mutations or pathway reactivation.
• Specificity and Toxicity: Ensuring that synthetic lethal therapies selectively target cancer cells without affecting normal cells is crucial to minimize side effects.

Future research aims to expand the repertoire of synthetic lethal interactions and develop novel therapeutic strategies to overcome resistance and improve specificity.

Related Pages

• Cancer therapy
• Genetic engineering
• DNA repair
• CRISPR
• BRCA1
• BRCA2