Synthetic lethal interactions of DEAD/H-box helicases as targets for cancer therapy

Abstract

DEAD/H-box helicases are implicated in virtually every aspect of RNA metabolism, including transcription, pre-mRNA splicing, ribosomes biogenesis, nuclear export, translation initiation, RNA degradation, and mRNA editing. Most of these helicases are upregulated in various cancers and mutations in some of them are associated with several malignancies. Lately, synthetic lethality (SL) and synthetic dosage lethality (SDL) approaches, where genetic interactions of cancer-related genes are exploited as therapeutic targets, are emerging as a leading area of cancer research. Several DEAD/H-box helicases, including DDX3, DDX9 (Dbp9), DDX10 (Dbp4), DDX11 (ChlR1), and DDX41 (Sacy-1), have been subjected to SL analyses in humans and different model organisms. It remains to be explored whether SDL can be utilized to identity druggable targets in DEAD/H-box helicase overexpressing cancers. In this review, we analyze gene expression data of a subset of DEAD/H-box helicases in multiple cancer types and discuss how their SL/SDL interactions can be used for therapeutic purposes. We also summarize the latest developments in clinical applications, apart from discussing some of the challenges in drug discovery in the context of targeting DEAD/H-box helicases.

DDX41: exploring the roles of a versatile helicase

“…Using patients’ data in The Cancer Genome Atlas, we have previously examined the expression of DDX41 in 24 different cancer types and found that DDX41 is up-regulated in most cancers [ 85 ]. In addition, we found that the predominant mutant DDX41 R525H protein has reduced ATP hydrolysis and DNA unwinding activities but retains normal strand annealing activity that causes excessive innate immune activation [ 69 ].…”

The exon-junction complex helicase eIF4A3 holds therapeutic potential in acute myeloid leukemia

“…Importantly, eIF4A3 was the only helicase found in our analysis and showed the highest degree of essentiality among members of the DEAD box family of enzymes (Supplementary Fig. S1A ), implicated in the treatment of both solid tumors and blood cancers [ 8 ].

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