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.

Predicting host-based, synthetic lethal antiviral targets from omics data

“…The presence of numerous paralogs in candidate SL genes also demands careful consideration due to potential functional redundancy hindering effective synthetic lethality. Interestingly, gene pairs that are paralogs have been found to engage in SL relationships more often than by chance ( 87 ). The prioritization of VIH–SL pairs can consider these aspects, with final candidates selected for their druggability and the availability of existing drugs or ligands (Table 6 ).…”

“…Both VPS25 and CHMP2A represent candidate pan-viral SL targets involved in multivesicular body assembly, which is directed by the ESCRT complex and has been shown to be involved in the early viral life cycle of multiple viruses ( 96–98 ). Furthermore, CHMP2A interacts with SARS-CoV-2 Orf9b and has been shown to contribute to the budding of a variety of viruses including HIV ( 87 ), equine infectious anemia virus ( 99 ), and murine leukemia virus ( 88 ), suggesting a critical role for virus release and thus a potential role as a pan-viral SL target. While these three candidate SL targets could be promising, none are listed as drug targets in DrugBank.…”

Proteomic Discovery of RNA-Protein Molecular Clamps Using a Thermal Shift Assay with ATP and RNA (TSAR)

“…We also found that DDX3Y, a male-specific paralog that shares 90% sequence similarity with DDX3X (82), is stabilized in parallel with DDX3X in both TSAR and LiP-MS, a finding afforded by our use of male-derived cell lysate. The apparent unity between DDX3X and DDX3Y targeting, at least among our compound panel, urges thorough structural evaluation for groups embarking on paralog-specific rocaglate discovery (83).…”

Using graph-based model to identify cell specific synthetic lethal effects

“…Specifically, paralogs, which arise from duplicated sequences of a shared ancestor and often perform similar functions, exhibit functional redundancy. Their loss is more common in tumors [51] , making them potential precision targets for cancer treatment and an essential dataset for SL discovery [52] , [53] . Mutually exclusive mutation patterns suggest incompatible driver mutations in tumorigenesis, indicating a potential source of SL interactions [54] .…”