Paralog-based synthetic lethality: rationales and applications

Abstract

Tumor cells can result from gene mutations and over-expression. Synthetic lethality (SL) offers a desirable setting where cancer cells bearing one mutated gene of an SL gene pair can be specifically targeted by disrupting the function of the other genes, while leaving wide-type normal cells unharmed. Paralogs, a set of homologous genes that have diverged from each other as a consequence of gene duplication, make the concept of SL feasible as the loss of one gene does not affect the cell's survival. Furthermore, homozygous loss of paralogs in tumor cells is more frequent than singletons, making them ideal SL targets. Although high-throughput CRISPR-Cas9 screenings have uncovered numerous paralog-based SL pairs, the unclear mechanisms of targeting these gene pairs and the difficulty in finding specific inhibitors that exclusively target a single but not both paralogs hinder further clinical development. Here, we review the potential mechanisms of paralog-based SL given their function and genetic combination, and discuss the challenge and application prospects of paralog-based SL in cancer therapeutic discovery.

Keywords: cancer therapy; clinical prospect; mechanism; paralog; synthetic lethality.

Figure 1

Schematic diagram of SL. Normal cells, devoid of gene A mutations, exhibit tolerance to gene B suppression, whereas tumor cells with gene A loss undergo gene B suppression, leading to cell death.

Figure 2

Genetic combination of paralog-based SL. (A) SL interactions within the paralog family. (B) SL interactions between paralog members and other genes. (C) SL interactions between a specific paralog member and other genes. (D) SL interactions between paralog members and other factors.

Figure 3

Some mechanisms of paralog-based SL. (A) Loss of core structures. (B) Loss of essential protein function. (C) The SL interaction of gene and its paralog or the regulator of its paralog. (D) Imbalance of two functions.

Figure 4

Impact factors and molecular mechanisms of paralog compensation. (A) Functional divergence and compensation capabilities of paralogs. (B) Active paralogous compensation forms (117).