The biology of DHX9 and its potential as a therapeutic target

Abstract

DHX9 is member of the DExD/H-box family of helicases with a "DEIH" sequence at its eponymous DExH-box motif. Initially purified from human and bovine cells and identified as a homologue of the Drosophila Maleless (MLE) protein, it is an NTP-dependent helicase consisting of a conserved helicase core domain, two double-stranded RNA-binding domains at the N-terminus, and a nuclear transport domain and a single-stranded DNA-binding RGG-box at the C-terminus. With an ability to unwind DNA and RNA duplexes, as well as more complex nucleic acid structures, DHX9 appears to play a central role in many cellular processes. Its functions include regulation of DNA replication, transcription, translation, microRNA biogenesis, RNA processing and transport, and maintenance of genomic stability. Because of its central role in gene regulation and RNA metabolism, there are growing implications for DHX9 in human diseases and their treatment. This review will provide an overview of the structure, biochemistry, and biology of DHX9, its role in cancer and other human diseases, and the possibility of targeting DHX9 in chemotherapy.

Keywords: DExD/H-box; DHX9; Maleless; RNA helicase A; helicase.

Figure 1. Helicase domain of DExD/H-box helicases and functional domains in DHX9

A. Conserved sequence motifs in the helicase core domain of DDX and DHX helicases. Consensus sequences are shown below some of the motifs. “x” represents any amino acid. The Q-motif is present in DDX but not DHX box helicases (including DHX9) and confers specificity for ATP binding. B. Schematic representation of DHX9 functional domains. Numbers indicate amino acid positions in human DHX9. dsRBD, double-stranded RNA binding domain; MTAD, minimal transactivation domain; HA2, helicase-associated domain 2; OB-fold, oligonucleotide/oligosaccharide-binding fold; NLS, nuclear localization signal; NES, nuclear export signal.

Figure 2. Conservation of DHX9 across various species

Multiple sequence alignment of DHX9 homologues from human (H. sapiens) (NCBI accession # NP_001348), bovine (B. taurus) (NP_776461), mouse (M. musculus) (NP_031868), Drosophila (D. melanogaster) (NP_476641), C. elegans (NP_495890), and Arabidopsis (A. thaliana) (NP_850154). Red text indicates residues that are identical in all species. Blue text indicates residues with high similarity amongst species. The sequence alignment was generated using T-Coffee and visualized with BoxShade.

Figure 3. Nucleic acid substrates unwound by DHX9

Schematic representation of nucleic acid substrates that can be remodeled by DHX9. DNA strands are coloured in red and RNA strands in blue. The biological processes in which the substrates occur are indicated. Substrates are arranged from top to bottom in approximate order of increasing complexity. See text for a detailed description.