DHX9

DHX9 Full Name

DEAH (Asp-Glu-Ala-His) box polypeptide 9

DHX9 Introduction

DHX9, also widely known as RNA helicase A (RHA) or nuclear DNA helicase II (NDH II), is one of the largest members of the DExD/H-box family of ATP-dependent helicases in human cells. Rather than being restricted to a single step of gene expression, DHX9 is a multitasking enzyme that unwinds double-stranded RNA, double-stranded DNA, and RNA-DNA hybrids, and it participates in transcription, pre-mRNA processing, translation, microRNA biogenesis, and the cellular response to DNA damage. Through direct interactions with RNA polymerase II, the transcriptional coactivators CBP/p300, and the tumor suppressor BRCA1, DHX9 couples helicase activity to the regulation of specific target genes and to the maintenance of genome stability. One of its most important protective duties is the resolution of R-loops, three-stranded structures formed when nascent RNA anneals to the template DNA strand; by dismantling these structures DHX9 prevents transcription-associated DNA breaks. DHX9 also restrains the mobility of Alu retroelements by unwinding the inverted-repeat structures they form in RNA, and it contributes to antiviral innate immune signaling. Not surprisingly, dysregulation of DHX9 has been connected to cancer, where its overexpression supports the growth and survival of tumor cells, making it an intensively studied target in oncology.

Figure 1. Phosphorylated DHX9 favors circRNA expression.(.Lin Y C, et al. 2020)

Multidomain Helicase Architecture and Catalytic Activities
The DHX9 polypeptide is organized into several functional modules that allow it to process diverse nucleic acid substrates.
Two double-stranded RNA-binding domains at the N-terminus recognize helical RNA and are critical for many of the enzyme's gene-regulatory functions.
The central portion contains the signature DExH-box helicase core together with accessory helicase domains that couple ATP hydrolysis to the directional translocation of the enzyme along its nucleic acid substrate.
An extended C-terminal region mediates interactions with protein partners, including RNA polymerase II, BRCA1, and the NFAR family of RNA-binding proteins, effectively tethering the helicase to sites of active transcription and DNA repair.
DHX9 hydrolyzes ATP to unwind substrates in a 3' to 5' direction, and it can act on long, structured RNAs as well as on DNA:RNA hybrids that arise during transcription.
The enzyme is predominantly nuclear, although it shuttles between nucleus and cytoplasm, and its activity is regulated by post-translational modifications that influence substrate selectivity and protein interactions.
This modular design explains how a single helicase can be redeployed for transcription, splicing, translation, microRNA processing, and genome maintenance depending on the cellular context.

Genome Stability, Innate Immunity, and Cancer Connections
A central physiological role of DHX9 is the suppression of transcription-associated genomic instability through the resolution of R-loops; when DHX9 is depleted, R-loop accumulation leads to DNA double-strand breaks and hypersensitivity to replication stress.
DHX9 also safeguards the genome by limiting the mobility of Alu retrotransposons, whose RNA transcripts form stable inverted-repeat structures that the helicase unwinds, preventing their retrotransposition and the insertional mutagenesis they cause.
In innate immunity, DHX9 contributes to the sensing of foreign nucleic acids and to the amplification of antiviral responses, functioning alongside cytosolic pattern recognition receptors such as RIG-I and MDA5.
Because RNA helicases participate in viral replication, DHX9 is also hijacked by several viruses, including HIV-1 and hepatitis C virus, to promote their gene expression.
In cancer, DHX9 expression is frequently elevated, and the helicase supports the proliferation, survival, and metastatic behavior of tumor cells in part by maintaining the expression of growth-promoting genes and by protecting cancer genomes from damaging R-loops.
The dependency of cancer cells on DHX9 has stimulated interest in small-molecule helicase inhibitors, which could selectively disable the enzyme in tumors while sparing normal cells that tolerate reduced DHX9 levels.

Alternate Names for DHX9

DHX9; DEAH (Asp-Glu-Ala-His) box polypeptide 9; DDX9, DEAD/H (Asp Glu Ala Asp/His) box polypeptide 9 (RNA helicase A, nuclear DNA helicase II; leukophysin) , LKP; ATP-dependent RNA helicase A; NDH II; RHA; leukophysin; DEAH box protein 9; nuclear DNA helicase II

• 1.Lin Y C, Yu Y S, Lin H H, et al. Oxaliplatin-induced DHX9 phosphorylation promotes oncogenic circular RNA CCDC66 expression and development of chemoresistance. Cancers, 2020, 12(3): 697.