Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Brai, Annalaura; Fazi, Roberta; Tintori, Cristina; Zamperini, Claudio; Bugli, Francesca; Sanguinetti, Maurizio; Stigliano, Egidio; Esté, José A.; Badía, Roger; Franco, Sandra; Martı́nez, Miguel Ángel; Martinez, Javier P; Meyerhans, Andreas; Saladini, Francesco; Zazzi, Maurizio; Garbelli, Anna; Maga, Giovanni; Botta, Maurizio

doi:10.1073/pnas.1522987113

Cited by 102 publications

(112 citation statements)

References 43 publications

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“…Under the condition of DNA damage and inflammation, aberration functions of DNA repair could promote the development of dysplastic lesion and subsequent HCC. Given that the small-molecule-mediated inhibition of DDX3X activity may provide new therapeutic opportunities to treat various viral infections and cancers (47,48), the impact of DDX3X on DNA damage and repair pathways cannot be underscored. A detailed understanding of the biology, pathology, and the complexity of the cellular responses to DNA damage in HCC associated with DDR deficiency will allow further preclinical investigations and provide appropriate treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

DNA Damage, Liver Injury, and Tumorigenesis: Consequences of DDX3X Loss

Chan

Chen²,

Lee

et al. 2019

Molecular Cancer Research

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The pleiotropic roles of DEAD-box helicase 3, X-linked (DDX3X), including its functions in transcriptional and translational regulation, chromosome segregation, DNA damage, and cell growth control, have highlighted the association between DDX3X and tumorigenesis. However, mRNA transcripts and protein levels of DDX3X in patient specimens have shown the controversial correlations of DDX3X with hepatocellular carcinoma (HCC) prevalence. In this study, generation of hepatocyte-specific Ddx3x-knockout mice revealed that loss of Ddx3x facilitates liver tumorigenesis. Loss of Ddx3x led to profound ductular reactions, cell apoptosis, and compensatory proliferation in female mutants at 6 weeks of age. The sustained phosphorylation of histone H2AX (gH2AX) and significant accumulation of DNA single-strand breaks and double-strand breaks in liver indicated that the replicative stress occurred in female mutants. Further chromatin immunoprecipitation analyses demonstrated that DDX3X bound to promoter regions and regulated the expression of DNA repair factors, DDB2 and XPA, to maintain genome stability. Loss of Ddx3x led to decreased levels of DNA repair factors, which contributed to an accumulation of unrepaired DNA damage, replication stress, and eventually, spontaneous liver tumors and DEN-induced HCCs in Alb-Cre/þ;Ddx3x flox/flox mice.Implications: These data identify an important role of DDX3X in the regulation of DNA damage repair to protect against replication stress in liver and HCC development and progression.

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Section: Discussionmentioning

confidence: 99%

DNA Damage, Liver Injury, and Tumorigenesis: Consequences of DDX3X Loss

Chan

Chen²,

Lee

et al. 2019

Molecular Cancer Research

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“…Other host targets. Several groups of compounds reported to target pleiotropic host targets, including ribosomes (lactimidomycin and its derivatives), the proteasome (bortezomib and its derivatives), DDX3 or HSP70, have demonstrated broad-spectrum antiflaviviral activity in vitro 12,15,118,231,232 . However, most of these compounds have side effects that severely limit their potential use as (prophylactic) antiviral agents.…”

Section: Polyamine Synthesis Inhibitorsmentioning

confidence: 99%

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

Boldescu

Behnam

Vasilakis³

et al. 2017

Nat Rev Drug Discov

254

217

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Infections with flaviviruses, such as dengue, West Nile virus, and the recently re-emerging Zika virus are an increasing and probably lasting global risk. This review summarizes and comments on the opportunities for broad-spectrum agents that are active against a range of flaviviruses. Broad-spectrum activity would be particularly desirable as preparatory measure for the next flaviviral epidemic that could emerge from as-yet-unknown or neglected viruses. Potential target sites for broad-spectrum anti-flaviviral compounds include viral proteins and host mechanisms that are exploited by these viruses during entry and replication. A variety of compounds with broad-spectrum antiviral activity have already been identified by target-specific or phenotypic assays. For some other compound classes, broad-spectrum activity can be anticipated because of their mode of action and molecular target(s).

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“…These findings indicate that aberrations in this gene result in loss of RNA-unwinding function and suppression of cell proliferation, thus contributing to the pathogenesis and poor prognosis of NKTCL. It has been reported that DDX3X is an important target for the development of broad-spectrum antiviral agents [38]. In lung cancer, a small molecule inhibitor (RK-33) targeting DDX3X was found to be effective in inducing apoptosis and promoting sensitization to radiation in DDX3X-overexpressing cell lines [39].…”

Section: Ddx3xmentioning

confidence: 99%

Frequent Mutations in Natural Killer/T Cell Lymphoma

Zhang¹,

Li²,

Xue³

et al. 2018

Cell Physiol Biochem

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Extranodal natural killer (NK)/T cell lymphoma (ENKTL-NT or NKTCL), with its aggressive nature and poor prognosis, has been widely studied to discover more effective treatment options. Various somatic gene alterations have been identified by traditional Sanger sequencing. However, recently, novel gene mutations in NKTCL have been revealed by next-generation sequencing (NGS) technology, suggesting the potential for novel targeted therapies. This review discusses recurrent aberrations in NKTCL detected by NGS, which can be categorized into three main groups, specifically, tumor suppressors (TP53, DDX3X, and MGA), the JAK/STAT cascade, and epigenetic modifiers (KMT2D, BCOR, ARID1A, and EP300). Some epigenetic dysregulation and DDX3X mutation, which have been rarely identified by traditional sequencing technology, were recently uncovered with high frequencies by NGS. In this review, we summarize the mutational frequencies of various genes in NKTCL. In general, based on our analysis, BCOR is the most frequently mutated gene (16.9%), followed by TP53 (14.7%), and DDX3X (13.6%). The characterization of such genes provides new insight into the pathogenesis of this disease and indicates new biomarkers or therapeutic targets.

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Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Cited by 102 publications

References 43 publications

DNA Damage, Liver Injury, and Tumorigenesis: Consequences of DDX3X Loss

DNA Damage, Liver Injury, and Tumorigenesis: Consequences of DDX3X Loss

Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond

Frequent Mutations in Natural Killer/T Cell Lymphoma

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