A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs

Huang, Chuan; Liang, Dongming; Tatomer, Deirdre C.; Wilusz, Jeremy E.

doi:10.1101/gad.314856.118

Cited by 284 publications

(215 citation statements)

References 38 publications

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“…To determine the subcellular localization of circE7, cells were fractionated and nuclear and cytoplasmic fractions confirmed with MALAT1 and 18S or β-actin, respectively. Consistent with the behavior of other translated circRNAs 20,22,23,24 , RT-PCR confirmed that the majority of circE7 (~60%) localized to the cytoplasm ( Fig. 2e).…”

Section: Resultssupporting

confidence: 80%

Translation and Transforming Activity of a Circular RNA from Human Papillomavirus

Lee

Kim

Chamseddin

et al. 2019

Preprint

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Bioinformatics and in vitro studies have revealed that single-stranded circular RNAs (circRNAs), generated through 'backsplicing,' occur more extensively than initially appreciated. While the functions of most circRNAs are unknown, binding of microRNAs (miRNA), regulation of splicing and transcription, and translation into proteins have all been demonstrated for specific circRNAs.Virally-derived circRNAs have recently been described in gamma-herpesviruses. Here, we report that oncogenic human papillomaviruses (HPV) generate circRNAs, including ones which encompass the entire coding region of the E7 oncogene (circE7). HPV16 circE7 can be detected by both inverse RT-PCR and Northern blots of HPV16-transformed cell lines. CircE7 is N 6 -methyladenosine (m 6 A) modified, preferentially localized to the cytoplasm, and can be translated to produce E7 oncoprotein. Specific disruption of circE7 in CaSki cervical carcinoma cells decreased E7 protein levels, inhibited cell proliferation, and inhibited the ability of the cells to form colonies in soft agar. Analysis of TCGA RNA-seq data demonstrates that HPV-positive cancers have abundant circE7 RNAs. These results provide evidence that virally-derived, protein-encoding circular RNAs have biologically important functions with relevance to the transforming properties of HPV.

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Section: Resultssupporting

confidence: 80%

Translation and Transforming Activity of a Circular RNA from Human Papillomavirus

Lee

Kim

Chamseddin

et al. 2019

Preprint

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“…Alurepeats in primates) or facilitated by interactions between flanking intronbound RNA-binding proteins (RBPs) 13,15,19 . circRNAs are largely localized to the cell cytoplasm [9][10][11][12][13][14] , and recent evidence suggests that nuclear export of circRNAs in human cells is influenced by the size of the given molecules 20 .…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, knockdown experiments have shown that nuclear export of larger circRNAs (>800 nucleotides) are dependent on DExH/D-box helicase UAP56 (DDX39B), whereas smaller species are dependent on URH49 (DDX39A) 20 .…”

Section: Introductionmentioning

confidence: 99%

circZNF827 nucleates a transcription inhibitory complex to balance neuronal differentiation

Hollensen

Thomsen

Marta

et al. 2019

Preprint

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Circular RNAs (circRNAs) comprise a large class of conserved non-codingRNAs that regulate a number of biological processes, including transcription, alternative splicing, translation and mRNA decay. circRNAs are enriched in the brain and mammalian cells subjected to neuronal differentiation markedly change their circRNA transcriptomes. Here, we have mapped high-confidence circRNA inventories of mouse embryonic stem cells, neuronal progenitor cells and in differentiated glutamatergic neurons and identify hundreds of differentially expressed circRNAs. Among several candidate circRNAs, knockdown of circZNF827 significantly induces expression of key neuronal markers, suggesting that this molecule negatively regulates neuronal differentiation. Using Nanostring analyses we demonstrate that among 770 tested genes linked to known neuronal pathways and neuropathological states, knockdown of circZNF827 deregulates expression of several genes including a robust upregulation of neuronal growth factor receptor (NGFR).We show that NGFR becomes transcriptionally upregulated and that this functionally enhances NGF signalling. Our results suggest that circZNF827, although being highly enriched in the cell cytoplasm, can elicit transcriptional changes, which in turn balances proliferation and neuronal differentiation signalling.

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“…The vast majority of circRNAs originate from exons, although there have been studies showing that they are produced from a variety of regions in the genome, including introns, exons, and UTR regions. The cytoplasm is host to the majority of circRNAs (Kristensen et al, 2018), but there is recent evidence of certain circRNAs enriched in the nucleus and controlled or modulated by sequence length (Huang et al, 2018). Interestingly, most circRNAs are not more abundant when compared to corresponding mRNA transcripts, but circRNAs exhibit greater half-lives demonstrating their increased stability (Kristensen et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The role of SRSF3 splicing factor in generating circular RNAs

Asnani

Black

et al. 2019

Preprint

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Circular RNAs (circRNAs) represent a novel class of non-coding RNAs that are emerging as potentially important regulators of gene expression. circRNAs are typically generated from host gene transcripts through a non-canonical back-splicing mechanism, whose regulation is still not well understood. To explore regulation of circRNAs in cancer, we generated sequence data from RNase R-resistant transcripts in human p493-6 B-lymphoid cells and identified thousands of novel as well as previously identified circRNAs. Approximately 40% of expressed genes generated a circRNA, with half of them generating multiple isoforms, suggesting the involvement of alternative back-splicing and regulatory RNA-binding proteins (RBPs). We observed that genes generating circRNAs with back-spliced exonic junctions were enriched for RBP recognition motifs, including multiple splicing factors, most notably SRSF3, a splicing factor known to promote exon inclusion. To test the role of SRSF3 role in circRNA production, we performed traditional RNA-seq in p493-6 B-lymphoid cells with and without SRSF3 knockdown, and identified 926 mRNA transcripts, whose canonical splicing was affected by SRSF3. We found that a subset (205) of these SRSF3 targets served as host transcripts for circRNA, suggesting that SRSF3 may regulate exon circularization. Since this splicing factor is deregulated in hematologic malignancies, we hypothesize that SRSF3-dependent circRNAs, similar to their mRNA counterparts, might contribute to the pathogenesis of lymphomas and leukemias.

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A length-dependent evolutionarily conserved pathway controls nuclear export of circular RNAs

Cited by 284 publications

References 38 publications

Translation and Transforming Activity of a Circular RNA from Human Papillomavirus

Translation and Transforming Activity of a Circular RNA from Human Papillomavirus

circZNF827 nucleates a transcription inhibitory complex to balance neuronal differentiation

The role of SRSF3 splicing factor in generating circular RNAs

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