Targeting mitochondrial RNAs enhances the efficacy of the DNA-demethylating agents DOI Creative Commons

Stephanie Tan,

Sujin Kim, Yoosik Kim

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Dec. 28, 2024

Hypomethylating agents (HMAs) such as azacytidine and decitabine are FDA-approved chemotherapy drugs for hematologic malignancy. By inhibiting DNA methyltransferases, HMAs reactivate tumor suppressor genes (TSGs) endogenous double-stranded RNAs (dsRNAs) that limit growth trigger apoptosis via viral mimicry. Yet, show limited effects in many solid tumors despite the strong induction of TSGs dsRNAs. Here we targeting mitochondrial (mtRNAs) can enhance HMA-mediated cell death lung adenocarcinoma cells. We find HMA treatment accompanies increased mtRNA levels subsequent enhancement metabolic activity, resulting higher ATP production. Compromising function by downregulating mature expression HMAs. further perform a CRISPR screening on processing factors polymerase (POLRMT) ElaC Ribonuclease Z 2 (ELAC2) depleted cells sensitivity to suppressing decitabine-triggered Moreover, small molecular inhibitor POLRMT compromises activity synergistically enhances cytotoxicity Our study unveils insensitivity through elevation mtRNAs suggests regulatory potential synergistic targets improve therapeutic benefit

Language: Английский

A sequence of SVA retrotransposon insertions in ASIP shaped human pigmentation DOI Creative Commons
Nolan Kamitaki, Margaux L.A. Hujoel, Ronen E. Mukamel

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(8), P. 1583 - 1591

Published: July 24, 2024

Abstract Retrotransposons comprise about 45% of the human genome 1 , but their contributions to trait variation and evolution are only beginning be explored 2,3 . Here, we find that a sequence SVA retrotransposon insertions in an early intron ASIP (agouti signaling protein) gene has probably shaped pigmentation several times. In UK Biobank ( n = 169,641), recent 3.3-kb insertion polymorphism associated strongly with lighter skin (0.22 [0.21–0.23] s.d.; P 2.8 × 10 −351 ) increased cancer risk (odds ratio 1.23 [1.18–1.27]; 1.3 −28 ), appearing underlie one strongest common genetic influences on these phenotypes within European populations 4–6 expression displayed same association pattern, allele exhibiting 2.2-fold (1.9–2.6) expression. This effect had unusual apparent mechanism: earlier, nonpolymorphic, human-specific 3.9 kb upstream appeared have caused hypofunction by nonproductive splicing, which new (polymorphic) largely eliminated. Extended haplotype homozygosity indicated risen frequencies up 11% over past thousand years. These results indicate contributed species-wide increase, then local decrease, pigmentation.

Language: Английский

Citations

4
Retrotransposon life cycle and its impacts on cellular responses DOI Creative Commons
Ahmad Luqman-Fatah,

Kei Nishimori,

Shota Amano

et al.

RNA Biology, Journal Year: 2024, Volume and Issue: 21(1), P. 11 - 27

Published: Oct. 13, 2024

Approximately 45% of the human genome is comprised transposable elements (TEs), also known as mobile genetic elements. However, their biological function remains largely unknown. Among them, retrotransposons are particularly abundant, and some copies still capable mobilization within through RNA intermediates. This review focuses on life cycle summarizes regulatory mechanisms impacts cellular processes. Retrotransposons generally epigenetically silenced in somatic cells, but transcriptionally reactivated under certain conditions, such tumorigenesis, development, stress, ageing, potentially leading to instability. We explored dual nature genomic parasites elements, focusing roles diversity innate immunity. Furthermore, we discuss how host factors regulate retrotransposon cDNA intermediates binding, modification, degradation. The interplay between machinery provides insight into complex regulation potential for dysregulation cause aberrant responses inflammation autoimmune diseases.

Language: Английский

Citations

3
Nuclear Retention and Rna Editing Suppress the Recognition of Undegraded Intron Lariats as Non-Self DOI
Keonyong Lee, Jayoung Ku,

Soo Young Park

et al.

Published: Jan. 1, 2025

Language: Английский

Citations

0
Cellular dsRNA interactome captured by K1 antibody reveals the regulatory map of exogenous RNA sensing DOI Creative Commons

JinA Lim,

Namseok Lee,

Seonmin Ju

et al.

Communications Biology, Journal Year: 2025, Volume and Issue: 8(1)

Published: March 7, 2025

RNA-binding proteins (RBPs) provide a critical post-transcriptional regulatory layer in determining RNA fate. Currently, UV crosslinking followed by oligo-dT pull-down is the gold standard identifying RBP repertoire of poly-adenylated RNAs, but such method ineffective capturing RBPs that recognize double-stranded RNAs (dsRNAs). Here, we utilize anti-dsRNA K1 antibody immunoprecipitation quantitative mass spectrometry to comprehensively identify bound cellular dsRNAs without external stimulus. Notably, our dsRNA interactome contains involved sensing N6-methyladenosine and stress granule components. We further perform targeted CRISPR-Cas9 knockout functional screening discover can regulate interferon (IFN) response during exogenous sensing. Interestingly, most dsRBPs promote IFN-β secretion stimulation act as antiviral factors HCoV-OC43 infection. Our capture provides an unbiased comprehensive characterization putative will facilitate understanding physiological pathological contexts. Exploration using studies these dsRBP candidates elucidate role immune responses their importance viral

Language: Английский

Citations

0
Nanopore Sequencing Solves an Elusive Case of Sotos Syndrome DOI Creative Commons

Pasquale Di Letto,

Alberto Budillon,

S. Rahman

et al.

American Journal of Medical Genetics Part A, Journal Year: 2025, Volume and Issue: unknown

Published: March 10, 2025

Sotos syndrome is a rare genetic disorder characterized by distinctive facial features, including broad and prominent forehead, dolichocephaly, learning disabilities ranging from mild to severe intellectual impairment. Affected individuals often show overgrowth in height head circumference over two standard deviations. The caused haploinsufficiency of the NSD1 gene, with no evidence heterogeneity date. Here we describe unsolved case child 4 years age clinical diagnosis syndrome. However, trio exome sequencing (ES) exon chromosomal microarray (CMA) analysis excluded both small large mutations gene. As part Telethon Undiagnosed Programme, used additional tools investigate possibility new genes or elusive that may have been missed previous molecular diagnostic approaches. Therefore, performed Nanopore long-read sequencing. This revealed 447 bp insertion 13 mRNA confirmed in-frame skipping encodes for PHD domains. genomic shows 100% identity an intronic region, although inverted, containing AluSx1 element 2 kb upstream skipped exon, which drive event masking splice acceptor site 13. Interestingly, this first linked pathogenic mechanism involving enclosing transposable generating protein devoid PHDs, are required reading histone post-translational modifications.

Language: Английский

Citations

0
Inverted Alu repeats in loop-out exon skipping across hominoid evolution DOI Creative Commons
Danielle Denisko, Jeong‐Hyeon Kim, Jayoung Ku

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Changes in RNA splicing over the course of evolution have profoundly diversified functional landscape human genome. While DNA sequences proximal to intron-exon junctions are known be critical for splicing, impact distal intronic remains underexplored. Emerging evidence suggests that inverted pairs Alu elements can promote exon skipping by forming stem-loop structures. However, their prevalence and influence throughout remain unknown. Here, we present a systematic analysis across genome assess on through predicted formation relevance hominoid evolution. We found pairs, particularly AluY-AluSx1 AluSz-AluSx, enriched flanking regions skippable exons genome-wide form stable Exons defined weak 3' acceptor strong 5' donor splice sites appear especially prone this mechanism. Through comparative nine primate species, identified 67,126 hominoid-specific insertions, primarily from AluY AluS subfamilies, which genes ubiquitination-related pathways. Experimental validation among several further reinforced potential evolutionary significance. This work extends our current knowledge roles secondary structure formed details newly emerging mechanism transposable contributed genomic innovation at transcriptomic level.

Language: Английский

Citations

0
Cooperative role of PACT and ADAR1 in preventing aberrant PKR activation by self-derived double-stranded RNA DOI Creative Commons
Lavanya Manjunath, Gisselle Santiago, Pedro Ortega

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 5, 2025

Language: Английский

Citations

0
Characterization of dsRNA binding proteins through solubility analysis identifies ZNF385A as a dsRNA homeostasis regulator DOI Creative Commons
Na Jiang, Hongqin Yang, Yi Lei

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: April 11, 2025

Double-stranded RNA (dsRNA) binding proteins (dsRBPs) play crucial roles in various cellular processes, especially the innate immune response. Comprehensive characterization of dsRBPs is essential to understand intricate mechanisms for dsRNA sensing and Traditional methods have predominantly relied on affinity purification, favoring isolation strong binders. Here, we adopt proteome integral solubility alteration (PISA) workflow characterizing dsRBPs, resulting observation 18 known identification 200 potential dsRBPs. Next, focus zinc finger protein 385 A (ZNF385A) discover that its knockout activates transcription interferon-β absence immunogenic stimuli. The ZNF385A elevates level endogenous dsRNAs, transcripts associated with retroelements, such as short interspersed nuclear element (SINE), long (LINE), terminal repeat (LTR). Moreover, loss enhances bioactivity 5-Aza-2'-deoxycytidine (5-AZA-CdR) tumor-killing effect NK cells. Our findings greatly expand dsRBP reservoir contribute understanding homeostasis.

Language: Английский

Citations

0
Splice-switching ASOs targeting an Alu-derived exon in theAURKA5’UTR collapse an SRSF1-AURKA-MYC oncogenic circuit in pancreatic cancer DOI
Alexander J. Kral, Jia Lu, GeunYoung Sim

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, driven by oncogenic KRAS mutations and dysregulated oncogenes, such as SRSF1 , MYC AURKA . Although KRAS-targeted therapies are in development, resistance mechanisms underscore the need to identify alternative vulnerabilities. Here, we uncover an SRSF1-AURKA-MYC circuit, wherein regulates 5’UTR splicing, enhancing protein expression; positively post-translationally, independently of its kinase activity; turn transcriptionally upregulates both Elevated tumor cells promotes inclusion exonized Alu exon 5’UTR, resulting splicing-dependent mRNA accumulation exon-junction- complex deposition. Modulating splicing with splice-switching antisense oligonucleotides (ASOs) collapses reducing PDAC cell viability triggering apoptosis. Our findings critical regulatory node highlight ASO-mediated potential therapeutic strategy that simultaneously targets oncogenes.

Language: Английский

Citations

0
The role of circular RNAs in regulating cytokine signaling in cancer DOI Creative Commons
Vandana Joshi,

Swati Swati,

Amit Mishra

et al.

FEBS Open Bio, Journal Year: 2025, Volume and Issue: unknown

Published: May 12, 2025

Dysregulation of cytokine signaling is central to the development and progression cancer. Cytokines are not only involved in promoting cancer but also regulate anti‐tumor immune responses. Circular RNAs (circRNAs) single‐stranded, covalently closed RNA molecules lacking free ends, which have emerged as critical regulators signaling. Transcriptional post‐transcriptional regulation by circRNAs contributes pathogenesis. Here, we discuss emerging role modulating pathways that development. In particular, examine TGF‐β, IL‐6, IL‐10, TNF‐α, VEGF, FGF, PDGF, chemokine

Language: Английский

Citations

0