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PubMed2026

DDX3X overexpression in mice can cause rapid tissue-specific toxicity and mortality.

DEAD-Box Helicase 3 X-Linked (DDX3X) is a ubiquitously expressed RNA helicase with diverse cellular roles implicated in a neurodevelopmental disorder called DDX3X syndrome. Although DDX3X is a leading genetic cause of intellectual disability in females, there is no treatment. While gene supplementation is a plausible therapeutic strategy, previous studies suggest DDX3X is carefully regulated and dose sensitive. To understand the consequences of overexpressing DDX3X with unregulated adeno-associated virus-mediated gene supplementation, we generated a vector driving strong ubiquitous DDX3X expression and administered it through a direct cerebrospinal fluid injection in newborn mice. Mice injected with a high dose died within 1 week from myocardial degeneration. Increased expression of stress response markers together with elevated apoptotic signaling in the heart suggested activation of stress-induced apoptotic pathways. Incidental findings included excess lipid accumulation, most prominent in the liver, and other liver injury. The innate immune system was also highly activated in the heart and liver. Interestingly, the brain was overall unaffected. The results suggest that DDX3X overexpression can cause rapid transgene-driven, tissue-specific toxicity, underscoring the need for tight DDX3X gene dosage control. These findings illustrate the possibility for improper transgene expression to drive severe toxicity including death within days following administration.

Animals↗

PubMed2004

Human DDX3Y, the Y-encoded isoform of RNA helicase DDX3, rescues a hamster temperature-sensitive ET24 mutant cell line with a DDX3X mutation.

We investigated the function of DDX3Y, the Y chromosome AZFa region encoding a putative DEAD-box RNA helicase protein, the loss of which results in oligozoospermia or azoospermia in humans. The human DDX3Y amino acid sequence is similar to that of the X chromosome gene DDX3X (91.7% homology). Here we report that human Y- and X-encoded DEAD box RNA helicase proteins DDX3Y and DDX3X are interchangeable and have an essential function: both proteins rescued a temperature-sensitive mutant hamster cell line (tsET24) that was otherwise incapable of growth at a nonpermissive temperature. Mouse homologues Ddx3y and D1Pas1-PL10 also rescued the mutant cell line at a nonpermissive temperature. In situ hybridization revealed that Ddx3x mRNA was expressed in almost every cell in mouse testis, suggesting that Ddx3x is involved in spermatogenesis. A comparative study of DDX3X and DDX3Y was performed to determine the significance of DDX3Y for cell growth and spermatogenesis. Both DDX3X and DDX3Y promoter DNAs produced a similar degree of transcription in vivo, whereas deletion studies of the promoter DNAs indicated that these genes are differentially regulated. DDX3Y, similar to DDX3X, shuttles between the nucleus and cytoplasm in a crm1-dependent manner.

Active Transport, Cell Nucleus↗

PubMed2025

DDX3X acts as a selective dual switch regulator of mRNA translation in acute ER stress.

Regulation of eukaryotic mRNA translation initiation greatly impacts gene expression and is critical for cellular stress response. DDX3X is a ubiquitous DEAD-box RNA helicase whose precise role in scanning and translation regulation in non-stressed and stressed cells remains incompletely understood. Here, we show that DDX3X associates with thousands of mRNAs as part of the eIF4F-mediated 48S scanning complex and exerts dual regulatory effects, promoting or repressing translation of select mRNAs under basal conditions and reversing this regulation during acute endoplasmic reticulum stress. Initiation profiling reveals mechanistically distinct modes of DDX3X action linked to its binding patterns across the 5' UTR and coding sequence. We further uncover that mRNAs selectively regulated by DDX3X exhibit specific patterns of cytidine N4-acetylation near start codons, with shared de-repression observed upon NAT10 knockdown. Together, our findings reveal DDX3X as a context-sensitive regulator that has a possible functional connection with epitranscriptomic features in translation control.

DEAD-box RNA Helicases↗

PubMed2026

Identification of highly immunogenic endogenous dsRNAs from cellular MDA5 filaments.

ADAR1 converts adenosine to inosine in endogenous double-stranded RNAs (dsRNAs) to prevent excessive MDA5-driven interferon-stimulated gene expression. The source of endogenous immunogenic dsRNAs remains enigmatic because only a small fraction of ADAR1 substrates activate MDA5, and cellular MDA5 filaments have not been isolated. Here, we couple affinity purification of cellular MDA5 filaments with RNA sequencing to define immunogenic endogenous dsRNAs. Greater than 84% of dsRNAs suppressed by combined DDX3X RNA helicase and ADAR1 base-editing activities were present in MDA5 filaments, compared to less than 1% of dsRNA substrates acted on by ADAR1 alone. Dual substrate dsRNAs consisted of inverted repeats embedded in 3'-UTRs with high base-pair complementarity and longer intervening sequences between repeats, with a minor contribution coming from intermolecular dsRNAs formed by sense and antisense transcripts. Moreover, the majority of dual substrate immunogenic dsRNAs were hyperedited in DDX3X mutant cancers. This reveals the identity of endogenous immunogenic dsRNAs and quality control mechanisms underlying their suppression.

Journal Article↗

PubMed2005

RNA helicases: regulators of differentiation.

RNA helicases are highly conserved enzymes that utilize the energy derived from NTP hydrolysis to modulate the structure of RNA. RNA helicases participate in all biological processes that involve RNA, including transcription, splicing and translation. Based on the sequence of the helicase domain, they are classified into families, such as DDX and DHX families of human RNA helicases. The specificity of RNA helicases to their targets is likely due to several factors, such as the sequence, interacting molecules, subcellular localization and the expression pattern of the helicases. There are several examples of the involvement of RNA helicases in differentiation. Human DDX3 has two closely related genes designated DDX3Y and DDX3X, which are localized to the Y and X chromosomes, respectively. DDX3Y protein is specifically expressed in germ cells and is essential for spermatogenesis. DDX25 is another RNA helicase which has been shown to be required for spermatogenesis. DDX4 shows specific expression in germ cells. The Drosophila ortholog of DDX4, known as vasa, is required for the formation of germ cells and oogenesis by a mechanism that involves regulating the translation of mRNAs essential for differentiation. Abstrakt is the Drosphila ortholog of DDX41, which has been shown to be involved in visual and CNS system development. DDX5 (p68) and its related DDX17 (p72) have also been implicated in organ/tissue differentiation. The ability of RNA helicases to modulate the structure and thus availability of critical RNA molecules for processing leading to protein expression is the likely mechanism by which RNA helicases contribute to differentiation.

Animals↗

PubMed2004

The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control.

We explored the function of the human DEAD-box Y RNA helicase DBY (DDX3Y) gene located in the (AZFa) region on the human Y chromosome (Yq11.21). Deletion of this Y interval is known to be a major cause for the occurrence of a severe testicular pathology, the Sertoli-cell-only (SCO) syndrome. DBY has a structural homologue on the short arm of the X chromosome DBX (DDX3X) (Xp11.4). We found widespread transcription of both genes in each tissue analyzed, although predominantly in testis tissue. However, translation of DBY was detected only in the male germ line, whereas DBX protein was expressed in all tissues analyzed. In testis tissue sections, DBY protein was found predominantly in spermatogonia, whereas DBX protein was expressed after meiosis in spermatids. We conclude that although both RNA helicases are structurally very similar, they have diverged functionally to fulfill different roles in the RNA metabolism of human spermatogenesis, and that deletion of the DBY gene is the most likely cause of the severe testicular pathology observed in men with AZFa deletions.

Chromosomes, Human, Y↗

PubMed2006

Structural characterization and expression studies of Dby and its homologs in the mouse.

In spite of recent evidence showing the importance of DBY (DEAD-box RNA helicase Y) in spermatogenesis in human, the biologic role of its homolog Dby (also known as Ddx3y) in the mouse is less clear. The present study aims at characterizing the molecular structure of Dby and comparing its expression with its X- and autosome-linked homologs in embryonic gonads and developing germ cells in mice. Molecular cloning by rapid amplification of 3'-cDNA ends showed that the Dby gene in the mouse gives rise to 2 transcripts that differ only in the length of the 3'-untranslated region as a consequence of the use of alternative polyadenylation signals. Measurement by quantitative real-time polymerase chain reaction showed that both transcripts were ubiquitously expressed and were present in male germ cells and Sertoli cells. They were more abundant in type A spermatogonia compared with pachytene spermatocytes and round spermatids. Expression of Dby in the embryonic gonad increased from day 10.5 and reached a peak at day 17.5. The expression level of Dby decreased after birth and remained low in adult male gonads. Although the level of expression of Dby was much lower than its X chromosome homolog, Ddx3 (also known as Ddx3x) in all samples examined, the pattern of expression of the 2 genes was comparable. In contrast, their autosomal homolog, D1Pas1(also known as PL10), was predominantly expressed in pachytene spermatocytes and round spermatids. This result is in accord with meiotic sex chromosome inactivation in that Dby and Ddx are replaced in pachytene spermatocytes by their autosomal retroposon. These observations indicate that unlike DBY in humans, the role of Dby in spermatogenesis is less obvious in the mouse and its biologic activity may be replaced by that of Ddx3 and D1Pas1.

Amino Acid Sequence↗