ISG20 and nuclear exosome promote destabilization of nascent transcripts for spliceosomal U snRNAs and U1 variants

Kawamoto, Takahito; Yoshimoto, Rei; Taniguchi, Ichiro; Kitabatake, Makoto; Ohno, Masatomi

doi:10.1111/gtc.12817

Cited by 5 publications

(4 citation statements)

References 30 publications

(48 reference statements)

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“…Variant genes are potentially mis-processed and targeted for decay by the nuclear exosome. U1 variant vU1-15 has been shown to have a half-life of only 10 min, in agreement with our findings (Supplemental Table S4), and knockdown of the nuclear exosome doubles its half-life (Kawamoto et al 2020;Lardelli and Lykke-Andersen 2020). The deadenylase TOE1 antagonizes exosomal degradation of snRNAs, but appears to act preferentially on canonical snRNAs compared to variants (Lardelli and Lykke-Andersen 2020).…”

Section: Variant Snrna Incorporation Into Spliceosomes Is Influenced ...supporting

confidence: 91%

Human spliceosomal snRNA sequence variants generate variant spliceosomes

Mabin

Lewis

Brow

et al. 2021

RNA

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Human pre-mRNA splicing is primarily catalyzed by the major spliceosome, comprising five small nuclear ribonucleoprotein complexes, U1, U2, U4, U5, and U6 snRNPs, each of which contains the corresponding U-rich snRNA. These snRNAs are encoded by large gene families exhibiting significant sequence variation, but it remains unknown if most human snRNA genes are untranscribed pseudogenes or produce variant snRNAs with the potential to differentially influence splicing. Since gene duplication and variation are powerful mechanisms of evolutionary adaptation, we sought to address this knowledge gap by systematically profiling human U1, U2, U4, and U5 snRNA variant gene transcripts. We identified 55 transcripts that are detectably expressed in human cells, 38 of which incorporate into snRNPs and spliceosomes in 293T cells. All U1 snRNA variants are more than 1000-fold less abundant in spliceosomes than the canonical U1, whereas at least 1% of spliceosomes contain a variant of U2 or U4. In contrast, eight U5 snRNA sequence variants occupy spliceosomes at levels of 1% to 46%. Furthermore, snRNA variants display distinct expression patterns across five human cell lines and adult and fetal tissues. Different RNA degradation rates contribute to the diverse steady state levels of snRNA variants. Our findings suggest that variant spliceosomes containing noncanonical snRNAs may contribute to different tissue- and cell-type–specific alternative splicing patterns.

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Section: Variant Snrna Incorporation Into Spliceosomes Is Influenced ...supporting

confidence: 91%

Human spliceosomal snRNA sequence variants generate variant spliceosomes

Mabin

Lewis

Brow

et al. 2021

RNA

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“…PAMPs, including lipopolysaccharide, dsRNA, double-stranded DNA, CpG DNA, and single-stranded RNA, can induce IFN-β production. Considering the function of ISG20 in degrading hepatitis B virus (HBV) epsilon RNA and spliceosomal U small nuclear RNA molecules (snRNAs), we hypothesized that endogenous dsRNA could function as a mediator between ISG20 and IFN-β ( 24 , 41 ). Sensors of dsRNA mainly include MDA5, toll-like receptor 3 (TLR3), and RIG-I.…”

Section: Resultsmentioning

confidence: 99%

ISG20 stimulates anti-tumor immunity via a double-stranded RNA-induced interferon response in ovarian cancer

Chen

Jia

et al. 2023

Front. Immunol.

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Augmentation of endogenous double-stranded RNA (dsRNA) has become a promising strategy for activating anti-tumor immunity through induction of type I interferon (IFN) in the treatment of ovarian carcinoma. However, the underlying regulatory mechanisms of dsRNA in ovarian carcinoma remain elusive. From The Cancer Genome Atlas (TCGA), we downloaded RNA expression profiles and clinical data of patients with ovarian carcinoma. Using the consensus clustering method, patients can be classified by their expression level of core interferon-stimulated genes (ISGs): IFN signatures high and IFN signatures low. The IFN signatures high group had a good prognosis. Gene set enrichment analysis (GSEA) showed that differentially expressed genes (DEGs) were primarily associated with anti-foreign immune responses. Based on results from protein-protein interaction (PPI) networks and survival analysis, ISG20 was identified as a key gene involved in host anti-tumor immune response. Further, elevated ISG20 expression in ovarian cancer cells led to increased IFN-β production. The elevated interferon improved the immunogenicity of tumor cells and generated chemokines that attract immune cells to infiltrate the area. Upon overexpression of ISG20, endogenous dsRNA accumulated in the cell and stimulated IFN-β production through the Retinoic acid-inducible gene I (RIG-I)-mediated dsRNA sense pathway. The accumulation of dsRNA was associated with the ribonuclease activity of ISG20. This study suggests that targeting ISG20 is a potential immune therapeutic approach to treat ovarian cancer.

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“…These extensions serve as central hubs for quality control, where competing 3'-to-5' exonucleases that promote maturation or degradation dictate whether the small ncRNAs undergo processing to functional molecules [10][11][12][13] or are subjected to decay 12,14,15 . The competition between these processes can be influenced by post-transcriptional oligo(A) or -(U) tailing by terminal nucleotidyl transferases 12,[16][17][18][19] . A key question is what dictates the specificity of the exonucleases and terminal nucleotidyl transferases that act on small ncRNAs to ultimately control their fate.…”

Section: Introductionmentioning

confidence: 99%

The 3’ exonuclease TOE1 selectively processes snRNAs through recognition of Sm complex assembly and 5’ cap trimethylation

Ma,

Xiong,

Lardelli

et al. 2023

Preprint

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Competing exonucleases that promote 3′ end maturation or degradation direct quality control of small non-coding RNAs, but how these enzymes distinguish normal from aberrant RNAs is poorly understood. The Pontocerebellar Hypoplasia 7 (PCH7)-associated 3′ exonuclease TOE1 promotes maturation of canonical small nuclear RNAs (snRNAs). Here, we demonstrate that TOE1 achieves specificity towards canonical snRNAs by recognizing Sm complex assembly and cap trimethylation, two features that distinguish snRNAs undergoing correct biogenesis from other small non-coding RNAs. Indeed, disruption of Sm complex assembly via snRNA mutations or protein depletions obstructs snRNA processing by TOE1, and in vitro snRNA processing by TOE1 is stimulated by a trimethylated cap. An unstable snRNA variant that normally fails to undergo maturation becomes fully processed by TOE1 when its degenerate Sm binding motif is converted into a canonical one. Our findings uncover the molecular basis for how TOE1 distinguishes snRNAs from other small non-coding RNAs and explain how TOE1 promotes maturation specifically of canonical snRNAs undergoing proper processing.

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ISG20 and nuclear exosome promote destabilization of nascent transcripts for spliceosomal U snRNAs and U1 variants

Cited by 5 publications

References 30 publications

Human spliceosomal snRNA sequence variants generate variant spliceosomes

Human spliceosomal snRNA sequence variants generate variant spliceosomes

ISG20 stimulates anti-tumor immunity via a double-stranded RNA-induced interferon response in ovarian cancer

The 3’ exonuclease TOE1 selectively processes snRNAs through recognition of Sm complex assembly and 5’ cap trimethylation

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