Mapping the dsRNA World

Reich, Daniel P.; Bass, Brenda

doi:10.1101/cshperspect.a035352

Cited by 48 publications

(45 citation statements)

References 164 publications

(255 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These structures are identified by sensor proteins such as MDA5 and trigger the production of type I interferons as part of recruiting the innate immunity system [2,3]. However, large numbers of endogenous dsRNAs are likely to appear in normal eukaryotic cells as well [4], mainly due to the abundance of mobile elements in the genometranscripts harboring nearby inverted copies of the same repeat fold to create an endogenous dsRNA structure [5].…”

Section: Introductionmentioning

confidence: 99%

Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity

et al. 2020

View full text Add to dashboard Cite

Background: Mobile elements comprise a large fraction of metazoan genomes. Accumulation of mobile elements is bound to produce multiple putative double-stranded RNA (dsRNA) structures within the transcriptome. These endogenous dsRNA structures resemble viral RNA and may trigger false activation of the innate immune response, leading to severe damage to the host cell. Adenosine to inosine (A-to-I) RNA editing is a common posttranscriptional modification, abundant within repetitive elements of all metazoans. It was recently shown that a key function of A-to-I RNA editing by ADAR1 is to suppress the immunogenic response by endogenous dsRNAs.Results: Here, we analyze the transcriptomes of dozens of species across the Metazoa and identify a strong genomic selection against endogenous dsRNAs, resulting in their purification from the canonical transcriptome. This purifying selection is especially strong for long and nearly perfect dsRNAs. These are almost absent from mRNAs, but not pre-mRNAs, supporting the notion of selection due to cytoplasmic processes. The few long and nearly perfect structures found in human transcripts are weakly expressed and often heavily edited. Conclusion: Purifying selection of long dsRNA is an important defense mechanism against false activation of innate immunity. This newly identified principle governs the integration of mobile elements into the genome, a major driving force of genome evolution. Furthermore, we find that most ADAR1 activity is not required to prevent an immune response to endogenous dsRNAs. The critical targets of ADAR1 editing are, likely, to be found mostly in non-canonical transcripts.

show abstract

Section: Introductionmentioning

confidence: 99%

Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The findings in this study provide insights for the potential molecular mechanism of how DDX3X could regulate the cellular dsRNA homeostasis. Most endogenous dsRNAs are known to be located in the nucleus 7 or mitochondria 15 , so that cells prevent these dsRNAs from being exposed to the cytosolic dsRNA sensors and triggering a potentially detrimental innate immune responses. The nuclear-cytoplasmic dsRNA distribution data indicates that a small fraction of dsRNAs is present in the cytoplasm in the homeostatic condition without inducing an immune response, but the depletion of DDX3X substantially increases the level of cytoplasmic dsRNAs (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Failure to degrade the excess endogenous double-stranded RNAs (dsRNAs) is known to activate the cytoplasmic dsRNA sensors and trigger type I IFN response in the several types of cancer cells 3,7,9,12 . Because DDX3X is an RNA-binding protein, which has an activity for dsRNA unwinding, we speculated that DDX3X could impact the level of endogenous dsRNAs.…”

Section: Inhibiting Ddx3x Triggers the Accumulation Of Endogenous Doumentioning

confidence: 99%

“…5d). ADAR1 edits dsRNA (from Adenosine to Inosine) mostly in the nucleus, and most ADAR1-p110 is found in the nucleus 7,56 . Because DDX3X has been found mainly in the cytoplasm (Extended Data Fig.…”

Section: Dsrnamentioning

confidence: 99%

“…Advanced transcriptomics studies have shown that metazoan cells express various types of endogenous "self" dsRNAs such as endogenous retroviral elements (ERVs), repetitive RNA elements, mitochondrial dsRNAs, mRNAs with inverted Alu-containing 3' UTRs, and structural dsRNAs with long dsRNA stem [6][7][8][9][10][11] . Current evidence has revealed that abnormal accumulation of the endogenous dsRNAs in mammalian cells could trigger antiviral innate immune response through activation of dsRNA sensing pathways, such as MDA5 or PKR, and that this response could cause chronic inflammation and related human diseases 3,12,13 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhibiting DDX3X triggers tumor-intrinsic type I interferon response and enhances anti-tumor immunity

Choi

Kwon

Sun

et al. 2020

Preprint

View full text Add to dashboard Cite

Accumulating evidence has shown that cellular double-stranded RNAs (dsRNAs) induce antiviral innate immune responses in human normal and malignant cancer cells. However, it is not fully understood how endogenous ‘self’ dsRNA homeostasis is regulated in the cell. Here, we show that an RNA-binding protein, DEAD-box RNA helicase 3X (DDX3X), prevents the aberrant accumulation of cellular dsRNAs. Loss of DDX3X induces dsRNA sensor-mediated type I interferon signaling and innate immune response in breast cancer cells due to abnormal cytoplasmic accumulation of dsRNAs. Dual depletion of DDX3X and a dsRNA-editing protein, ADAR1 synergistically activates the cytosolic dsRNA pathway in breast cancer cell. Moreover, inhibiting DDX3X enhances the antitumor activity by increasing tumor intrinsic-type I interferon response, antigen presentation, and tumor-infiltration of cytotoxic T cells as well as dendritic cells in breast tumors, which may lead to the development of breast cancer therapy by targeting DDX3X in combination with immune checkpoint blockade.

show abstract

Unleashing viral mimicry: A combinatorial strategy to enhance the efficacy of PARP7 inhibitors

Manetsch,

Hottiger

2024

BioEssays

View full text Add to dashboard Cite

Cancer cells exploit mechanisms to evade immune detection triggered by aberrant self‐nucleic acids (NA). PARP7, a key player in this immune evasion strategy, has emerged as a potential target for cancer therapy. PARP7 inhibitors reactivate NA sensing, resulting in type I interferon (IFN) signaling, programmed cell death, anti‐tumor immunity, and tumor regression. Cancer cells with elevated IFN‐stimulated gene (ISG) scores, representing a viral mimicry‐primed state, are particularly sensitive to PARP7 inhibition. This review focuses on the endogenous sources of NA in cancer and the potential to exploit elevated aberrant self‐NA in cancer therapy. We describe strategies to increase cytoplamic NA levels, including targeting epigenetic control, DNA damage response, and mitochondrial function. We also discuss targeting RNA processing pathways, such as splicing and RNA editing, to enhance the immunostimulatory potential of existing NA. Combining PARP7 inhibitors with NA elevating strategies may improve cancer immunotherapy, especially for tumors with high ISG scores.

show abstract

Mapping the dsRNA World

Cited by 48 publications

References 164 publications

Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity

Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity

Inhibiting DDX3X triggers tumor-intrinsic type I interferon response and enhances anti-tumor immunity

Unleashing viral mimicry: A combinatorial strategy to enhance the efficacy of PARP7 inhibitors

Contact Info

Product

Resources

About