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Ribonuclease κ promotes longevity by preventing age-associated accumulation of circular RNA in stress granules

ABSTRACT: Circular RNAs (circRNAs) accumulate with age, but their functional impact on aging remains elusive. In this study, we reveal a mechanism by which ribonuclease κ (RNASEK) prevents age-dependent circRNA accumulation by promoting its degradation. Through a genetic screen targeting ribonucleases, we identified RNASEK as a specific circRNA-cleaving ribonuclease. RNASEK is downregulated during aging, causing the age-dependent increase in circRNA levels. RNASEK is necessary and sufficient for lifespan extension and healthspan maintenance in Caenorhabditis elegans. Mammalian RNASEK also directly degrades circRNAs, and is required for preventing premature aging in cultured human cells and mice, indicating its evolutionarily conserved role. Notably, we demonstrate that circRNAs localize within stress granules, where RNASEK, in collaboration with HSP90, prevents toxic aggregation of circRNAs in aged organisms. Our study establishes RNASEK as a conserved regulator of aging and offers a framework for targeting circRNAs to mitigate age-associated diseases and to extend organismal healthspan

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Seung-Jae V. Lee

PROVIDER: PXD073097 | iProX | Thu Jan 15 00:00:00 GMT 2026

REPOSITORIES: iProX

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Ribonuclease κ promotes longevity by preventing age-associated accumulation of circular RNA in stress granules [rnk-1]

Project description:Circular RNAs (circRNAs) accumulate with age, but their functional impact on aging remains elusive. In this study, we reveal a mechanism by which ribonuclease κ (RNASEK) prevents age-dependent circRNA accumulation by promoting its degradation. Through a genetic screen targeting ribonucleases, we identified RNASEK as a specific circRNA-cleaving ribonuclease. RNASEK is downregulated during aging, causing the age-dependent increase in circRNA levels. RNASEK is necessary and sufficient for lifespan extension and healthspan maintenance in Caenorhabditis elegans. Mammalian RNASEK also directly degrades circRNAs, and is required for preventing premature aging in cultured human cells and mice, indicating its evolutionarily conserved role. Notably, we demonstrate that circRNAs localize within stress granules, where RNASEK, in collaboration with HSP90, prevents toxic aggregation of circRNAs in aged organisms. Our study establishes RNASEK as a conserved regulator of aging and offers a framework for targeting circRNAs to mitigate age-associated diseases and to extend organismal healthspan.

2026-02-24 | GSE314234 | GEO

Ribonuclease κ promotes longevity by preventing age-associated accumulation of circular RNA in stress granules [rnk-1rnk-2_PARE]

2026-02-24 | GSE314237 | GEO

Ribonuclease κ promotes longevity by preventing age-associated accumulation of circular RNA in stress granules [rnk-1rnk-2]

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Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed

Project description:Circular RNAs (circRNAs) are an endogenous class of animal RNAs. Despite their abundance, their function and expression in the nervous system are unknown. Therefore, we sequenced RNA from different brain regions, primary neurons, isolated synapses, as well as during neuronal differentiation. Using these and other available data, we discovered and analyzed thousands of neuronal human and mouse circRNAs. circRNAs were extraordinarily enriched in the mammalian brain, well conserved in sequence, often expressed as circRNAs in both human and mouse, and sometimes even detected in Drosophila brains. circRNAs were overall upregulated during neuronal differentiation, highly enriched in synapses, and often differentially expressed compared to their mRNA isoforms. circRNA expression correlated negatively with expression of the RNA-editing enzyme ADAR1. Knockdown of ADAR1 induced elevated circRNA expression. Together, we provide a circRNA brain expression atlas and evidence for important circRNA functions and values as biomarkers. To assess circRNA expression in mammalian brain, we sequenced and analyzed mouse brain regions (hippocampus, cerebellum, prefrontal cortex and olfactory bulb), various neuronal differentiation (mouse P19 and human SH-SY5Y cells) and maturation (mouse cortical neurons) stages, and subcellular compartments in mouse (synaptoneurosomal fraction, cytoplasmic fraction, whole brain lysate).

2015-04-24 | E-GEOD-65926 | biostudies-arrayexpress

Synthetic circular RNA functions as a miR-21 sponge to suppress gastric carcinoma cell proliferation

Project description:MicroRNA (miRNA) sponges containing miRNA complementary binding sites constitute a potentially useful strategy for miRNA-inhibition therapeutics in cancer patients. Recently, naturally occurring circular RNAs (circRNAs) have been revealed to function as efficient microRNA sponges. We hypothesized that synthetic circRNA sponges targeting oncomiRs could be constructed and used to achieve potentially therapeutic microRNA loss of function. In this study, linear RNA molecules containing five miR-21 binding sites were transcribed in vitro. After dephosphorylation by calf intestinal phosphatase and phosphorylation by T4 polynucleotide kinase, circRNA sponges were circularized using 5’-3’ end ligation by T4 RNA ligase 1. Synthetic circular sponge stability was assayed in the presence of RNase R or fetal bovine serum. Luciferase reporter and cell proliferation assays were performed to assess competitive inhibition of miR-21 activity by circRNA sponges in NCI-N87 gastric cancer cells. Tandem Mass Tag (TMT) labeling proteomics analysis and Western blotting were performed to delineate effects of circRNA sponges on miR-21 downstream targeted proteins. Our experiments revealed that artificial circRNA sponges can be synthesized using enzymatic ligation. These synthetic circRNA sponges are more resistant than their linear RNA counterparts to nuclease degradation in vitro. They effectively suppress the activity of miR-21 on its downstream protein targets, including the important cancer protein DAXX. Finally, they also inhibit gastric cancer cell proliferation. Our results suggest that synthetic circRNA sponges represent a rapid, effective, convenient strategy to achieve loss of miRNA function in vitro, with potential future therapeutic application in vivo.

2018-10-22 | PXD008584 | Pride

Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals

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2015-01-06 | E-GEOD-63823 | biostudies-arrayexpress

Annotation and functional clustering of circRNA expression in rhesus macaque brain during aging

Project description:The abundance and function of circular RNAs (circRNAs) in mammalian brain have been reported, but their alterations in the biology of brain aging remain elusive. Here, using deep RNA profiling with linear RNA digestion by RNase R we explored a comprehensive map of changes in circRNA expression in rhesus macaque (macaca mulatta) brain in two age groups from adult (10 y) to aged (20 y) periods. Total 17,050 well expressed, stable circRNAs were identified. Cluster analysis reveals that dynamic changes in circRNA expression show the spatial-, sex- and age-biased specificities. On the basis of separate profiling of the RNAs, age-related circRNAs show differential correlation to host mRNA expression. Furthermore, two voltage-dependent L- and R-type calcium channel gene-derived circCACNA2D1 and circCACNA1E negatively regulate their host mRNA expression. Our results demonstrate the power of changes in circRNA expression to reveal insights into a potentially circRNA-mediated regulatory mechanism underlying the biology of brain aging.

2018-11-26 | GSE94027 | GEO

Structured elements drive circular RNA translation and expand the human proteome, part3

Project description:The human genome encodes tens of thousands circular RNAs (circRNAs) whose levels correlate with many disease states. While studies have focused on the non-coding functions of circRNAs, emerging evidence suggests that a handful of circRNAs encode proteins. Translation canonically starts by recognition of mRNA 5â€™cap and scanning to the start codon; how circRNA translation initiates remains unclear. Here, we developed a high-throughput screen to systematically identify and quantify RNA sequences that can direct circRNA translation. We identify and validate over 17,000 circRNA internal ribosome entry sites (IRES) and reveal that 18S rRNA complementarity and a structured RNA element on the IRES are important for facilitating circRNA cap-independent translation. With genomic and peptidomic analyses of the IRES, we identified nearly 1,000 putative endogenous protein-coding circRNAs and hundreds of translational units encoded by these circRNAs. We further characterized circFGFR1p, a protein encoded by circFGFR1, functions as a negative regulator of FGFR1 to suppress cell growth under stress conditions. The circRNA proteome may be important links among circRNA, biological control, and disease.

2021-08-25 | PXD025233 | Pride

Structured elements drive circular RNA translation and expand the human proteome, part1

Project description:The human genome encodes tens of thousands circular RNAs (circRNAs) whose levels correlate with many disease states. While studies have focused on the non-coding functions of circRNAs, emerging evidence suggests that a handful of circRNAs encode proteins. Translation canonically starts by recognition of mRNA 5’cap and scanning to the start codon; how circRNA translation initiates remains unclear. Here, we developed a high-throughput screen to systematically identify and quantify RNA sequences that can direct circRNA translation. We identify and validate over 17,000 circRNA internal ribosome entry sites (IRES) and reveal that 18S rRNA complementarity and a structured RNA element on the IRES are important for facilitating circRNA cap-independent translation. With genomic and peptidomic analyses of the IRES, we identified nearly 1,000 putative endogenous protein-coding circRNAs and hundreds of translational units encoded by these circRNAs. We further characterized circFGFR1p, a protein encoded by circFGFR1, functions as a negative regulator of FGFR1 to suppress cell growth under stress conditions. The circRNA proteome may be important links among circRNA, biological control, and disease.

2021-08-23 | PXD024993 | Pride

Structured elements drive circular RNA translation and expand the human proteome, part4

Project description:The human genome encodes tens of thousands circular RNAs (circRNAs) whose levels correlate with many disease states. While studies have focused on the non-coding functions of circRNAs, emerging evidence suggests that a handful of circRNAs encode proteins. Translation canonically starts by recognition of mRNA 5’cap and scanning to the start codon; how circRNA translation initiates remains unclear. Here, we developed a high-throughput screen to systematically identify and quantify RNA sequences that can direct circRNA translation. We identify and validate over 17,000 circRNA internal ribosome entry sites (IRES) and reveal that 18S rRNA complementarity and a structured RNA element on the IRES are important for facilitating circRNA cap-independent translation. With genomic and peptidomic analyses of the IRES, we identified nearly 1,000 putative endogenous protein-coding circRNAs and hundreds of translational units encoded by these circRNAs. We further characterized circFGFR1p, a protein encoded by circFGFR1, functions as a negative regulator of FGFR1 to suppress cell growth under stress conditions. The circRNA proteome may be important links among circRNA, biological control, and disease.

2021-08-26 | PXD025203 | Pride

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