Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate RNA metabolism through phase separation

Shen, Hui; Yanas, Amber; Owens, Michael C.; Zhang, Celia; Fritsch, Clark; Fare, Charlotte M.; Copley, Katie E.; Shorter, James; Goldman, Yale E.; Liu, Kathy Fange

doi:10.1016/j.molcel.2022.04.022

Cited by 50 publications

(40 citation statements)

References 101 publications

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“…In sexual dimorphic helicases DDX3X and DDX3Y, DDX3Y was found to be more droplet oriented than DDX3X, because of the difference in IDR1 sequence. This difference also results in DDX3Y having a stronger ability to aggregate FUS than DDX3X ( 49 ). The FET family of proteins, consisting of FUS (TLS), EWS (EWSR1), and TAF15, participates in phase transitions at RNA storage sites and assembles into higher-order structures through RNA stimulation, functions that are impaired in humans and contribute to disease.…”

Section: Phase Separation Of Ddx3x Decides the Cell Fate Under Stressmentioning

confidence: 99%

Phase separation in innate immune response and inflammation-related diseases

Liu

et al. 2023

Front. Immunol.

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Inflammation induced by nonspecific pathogenic or endogenous danger signals is an essential mechanism of innate immune response. The innate immune responses are rapidly triggered by conserved germline-encoded receptors that recognize broad patterns indicative of danger, with subsequent signal amplification by modular effectors, which have been the subject of intense investigation for many years. Until recently, however, the critical role of intrinsic disorder-driven phase separation in facilitating innate immune responses went largely unappreciated. In this review, we discuss emerging evidences that many innate immune receptors, effectors, and/or interactors function as “all-or-nothing” switch-like hubs to stimulate acute and chronic inflammation. By concentrating or relegating modular signaling components to phase-separated compartments, cells construct flexible and spatiotemporal distributions of key signaling events to ensure rapid and effective immune responses to a myriad of potentially harmful stimuli.

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Section: Phase Separation Of Ddx3x Decides the Cell Fate Under Stressmentioning

confidence: 99%

Phase separation in innate immune response and inflammation-related diseases

Liu

et al. 2023

Front. Immunol.

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“…To disrupt nucleic acid structures, DEAD-box helicases use simple cycles of RNA duplex binding, unwinding, and release, while DEAH-box helicases function only as translocases in the 3’→5’ direction ( 17 ). In terms of their nucleic acid-related functions, both DEAD-box and DEAH-box proteins are implicated in virtually every aspect of RNA metabolic processes, including transcription ( 18 – 20 ), ribosomes biogenesis ( 21 , 22 ), small RNA process ( 23 , 24 ), pre-mRNA splicing ( 25 , 26 ), RNA storage and decay ( 27 , 28 ), nuclear export ( 29 – 31 ), liquid–liquid phase separation ( 32 – 34 ), RNA degradation ( 35 , 36 ), translation ( 37 – 42 ), and so on ( Figure 1B ). Some of them are also involved in DNA metabolism, such as DNA repair ( 43 – 47 ).…”

Section: Dead/h-box Helicasesmentioning

confidence: 99%

“…DDX3 has two paralogs, DDX3X on the X-chromosome and DDX3Y on the Y-chromosome. Sharing more than 90% identity, they are redundant for protein synthesis ( 155 ), cell proliferation and survival ( 156 ), and temperature-sensitive in hamster cell line ( 157 ), but distinct for liquid-liquid phase separation, dissolution, and translation repression ( 34 ). Interestingly, the combination of DDX3 inhibitor RK-33 and PARP inhibitor Olaparib causes SL in BRCA1-proficient breast cancer ( 148 ).…”

Section: Synthetic Lethal Interactions Of Dead/h-box Helicasesmentioning

confidence: 99%

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

et al. 2023

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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.

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“…In addition, while the conditional knockout of Ddx3x in hematopoietic cells was incompatible with survival for female mice, male mice survived but showed specific deficiencies, for instance in innate antimicrobial immunity or lymphopoiesis, indicating that some functional differences exist between the two proteins in adults (47,54,55). The most divergent region between the DDX3X and DDX3Y amino acid sequences is found in their N-terminal part containing the IDR1 (Figure 1) (19). Shen and colleagues have demonstrated that this IDR1 is involved in stress granule (SG) formation for both human DDX3X and DDX3Y, but that DDX3Y exhibits a weaker enzymatic activity and thus, promotes less dynamic SGs, causing a higher translational repression compared to DDX3X (19).…”

Section: Differences Between Ddx3x and Ddx3ymentioning

confidence: 99%

“…activity. First, there is a known Nuclear Export Sequence (NES) (19)(20)(21) in the N-terminal domain. The mutation of the leucine residues 19 or 21 in this region causes an accumulation of DDX3X in the nucleus.…”

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confidence: 99%

The RNA helicase DDX3 and its role in c-MYC driven germinal center-derived B-cell lymphoma

et al. 2023

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DDX3X is an RNA helicase with many functions in RNA metabolism such as mRNA translation, alternative pre-mRNA splicing and mRNA stability, but also plays a role as a regulator of transcription as well as in the Wnt/beta-catenin- and Nf-κB signaling pathways. The gene encoding DDX3X is located on the X-chromosome, but escapes X-inactivation. Hence females have two active copies and males only one. However, the Y chromosome contains the gene for the male DDX3 homologue, called DDX3Y, which has a very high sequence similarity and functional redundancy with DDX3X, but shows a more restricted protein expression pattern than DDX3X. High throughput sequencing of germinal center (GC)-derived B-cell malignancies such as Burkitt Lymphoma (BL) and Diffuse large B-cell lymphoma (DLBCL) samples showed a high frequency of loss-of-function (LOF) mutations in the DDX3X gene revealing several features that distinguish this gene from others. First, DDX3X mutations occur with high frequency particularly in those GC-derived B-cell lymphomas that also show translocations of the c-MYC proto-oncogene, which occurs in almost all BL and a subset of DLBCL. Second, DDX3X LOF mutations occur almost exclusively in males and is very rarely found in females. Third, mutations in the male homologue DDX3Y have never been found in any type of malignancy. Studies with human primary GC B cells from male donors showed that a loss of DDX3X function helps the initial process of B-cell lymphomagenesis by buffering the proteotoxic stress induced by c-MYC activation. However, full lymphomagenesis requires DDX3 activity since an upregulation of DDX3Y expression is invariably found in GC derived B-cell lymphoma with DDX3X LOF mutation. Other studies with male transgenic mice that lack Ddx3x, but constitutively express activated c-Myc transgenes in B cells and are therefore prone to develop B-cell malignancies, also showed upregulation of the DDX3Y protein expression during the process of lymphomagenesis. Since DDX3Y is not expressed in normal human cells, these data suggest that DDX3Y may represent a new cancer cell specific target to develop adjuvant therapies for male patients with BL and DLBCL and LOF mutations in the DDX3X gene.

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Sexually dimorphic RNA helicases DDX3X and DDX3Y differentially regulate RNA metabolism through phase separation

Cited by 50 publications

References 101 publications

Phase separation in innate immune response and inflammation-related diseases

Phase separation in innate immune response and inflammation-related diseases

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

The RNA helicase DDX3 and its role in c-MYC driven germinal center-derived B-cell lymphoma

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