The m6A reader YTHDC1 and the RNA helicase DDX5 control the production of rhabdomyosarcoma-enriched circRNAs

Dattilo, Dario; Timoteo, Gaia Di; Setti, Adriano; Giuliani, Andrea; Peruzzi, Giovanna; Nebot, Manuel Beltran; Centrón-Broco, Alvaro; Mariani, Davide; Mozzetta, Chiara; Bozzoni, Irene

doi:10.1038/s41467-023-37578-7

Cited by 26 publications

(8 citation statements)

References 72 publications

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“…Recent new publications further support the notion that DDX5 is a critical biomarker and target in specialized rare cancers. This includes (but may not be limited to) neuroblastoma [ 119 ], osteosarcoma [ 120 , 121 ], rhabdomyosarcoma (RMS) [ 122 , 123 ] and myeloproliferative neoplasms (MPN) [ 124 ]. These studies further demonstrate the advantage of using DDX5 as a target for anticancer drug development, since there are many special programs and mechanisms from the FDA and NIH to promote rare cancer drug development and commercialization.…”

Section: Introductionmentioning

confidence: 99%

Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Li,

Ling,

Chakraborty

et al. 2023

J Exp Clin Cancer Res

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There is increasing evidence indicating the significant role of DDX5 (also called p68), acting as a master regulator and a potential biomarker and target, in tumorigenesis, proliferation, metastasis and treatment resistance for cancer therapy. However, DDX5 has also been reported to act as an oncosuppressor. These seemingly contradictory observations can be reconciled by DDX5’s role in DNA repair. This is because cancer cell apoptosis and malignant transformation can represent the two possible outcomes of a single process regulated by DDX5, reflecting different intensity of DNA damage. Thus, targeting DDX5 could potentially shift cancer cells from a growth-arrested state (necessary for DNA repair) to apoptosis and cell killing. In addition to the increasingly recognized role of DDX5 in global genome stability surveillance and DNA damage repair, DDX5 has been implicated in multiple oncogenic signaling pathways. DDX5 appears to utilize distinct signaling cascades via interactions with unique proteins in different types of tissues/cells to elicit opposing roles (e.g., smooth muscle cells versus cancer cells). Such unique features make DDX5 an intriguing therapeutic target for the treatment of human cancers, with limited low toxicity to normal tissues. In this review, we discuss the multifaceted functions of DDX5 in DNA repair in cancer, immune suppression, oncogenic metabolic rewiring, virus infection promotion, and negative impact on the human microbiome (microbiota). We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues.

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Section: Introductionmentioning

confidence: 99%

Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Li,

Ling,

Chakraborty

et al. 2023

J Exp Clin Cancer Res

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“…Here, we found that DDX5 interacted not only with METTL3 but also with METTL14 to form a stable complex. Although a previous study showed that DDX5 worked as a mediator of the back-splicing reaction and as a co-factor of the m6A regulatory network (Dattilo et al, 2023 ), our data provided the first piece of evidence showing that RNA helicases regulate mRNA m6A modification by forming a stable m6A methyltransferase writer complex. Unlike DDX46, which inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus (Zheng et al, 2017 ), DDX5 suppresses bacterial-induced inflammation by regulating the building of an mRNA m6A ‘writer’.…”

Section: Discussionmentioning

confidence: 59%

DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection

Xu,

Liu,

Zhi

et al. 2024

EMBO Rep

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DExD/H-box helicases are crucial regulators of RNA metabolism and antiviral innate immune responses; however, their role in bacteria-induced inflammation remains unclear. Here, we report that DDX5 interacts with METTL3 and METTL14 to form an m6A writing complex, which adds N6-methyladenosine to transcripts of toll-like receptor (TLR) 2 and TLR4, promoting their decay via YTHDF2-mediated RNA degradation, resulting in reduced expression of TLR2/4. Upon bacterial infection, DDX5 is recruited to Hrd1 at the endoplasmic reticulum in an MyD88-dependent manner and is degraded by the ubiquitin-proteasome pathway. This process disrupts the DDX5 m6A writing complex and halts m6A modification as well as degradation of TLR2/4 mRNAs, thereby promoting the expression of TLR2 and TLR4 and downstream NF-κB activation. The role of DDX5 in regulating inflammation is also validated in vivo, as DDX5- and METTL3-KO mice exhibit enhanced expression of inflammatory cytokines. Our findings show that DDX5 acts as a molecular switch to regulate inflammation during bacterial infection and shed light on mechanisms of quiescent inflammation during homeostasis.

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“…RNA analyses were carried out as described by ref. 52 . Oligonucleotides used for this study are listed in Supplementary Data 4 .…”

Section: Methodsmentioning

confidence: 99%

M6A reduction relieves FUS-associated ALS granules

Di Timoteo,

Giuliani,

Setti

et al. 2024

Nat Commun

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motoneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by aggregation of mutant proteins, among which the RNA binding protein FUS. Here we show that, in neuronal cells and in iPSC-derived MN expressing mutant FUS, such inclusions are significantly reduced in number and dissolve faster when the RNA m6A content is diminished. Interestingly, stress granules formed in ALS conditions showed a distinctive transcriptome with respect to control cells, which reverted to similar to control after m6A downregulation. Notably, cells expressing mutant FUS were characterized by higher m6A levels suggesting a possible link between m6A homeostasis and pathological aggregates. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, an inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.

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The m6A reader YTHDC1 and the RNA helicase DDX5 control the production of rhabdomyosarcoma-enriched circRNAs

Cited by 26 publications

References 72 publications

Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection

M6A reduction relieves FUS-associated ALS granules

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