RESUMEN

BACKGROUND: The prognosis of patients with hepatocellular cancer is substantially correlated with the abnormal expression of growing long non-coding RNA small nucleolar host gene RNA (SNHG) families in liver cancer tissues. This study aimed to examine the relationship between SNHG expression and liver cancer prognosis. METHODS: After searching six internet databases, pertinent manuscripts were found based on inclusion and exclusion criteria. To determine whether SNHG expression levels affect liver cancer prognosis, raw data were collected and hazard ratios (HRs) and odds ratios (ORs) were calculated. The results were examined for potential publication bias using the sensitivity analysis and Beeg's test. RESULTS: Most SNHG family members were up-regulated in liver cancer tissues. High SNHG expression predicts poor liver cancer outcomes of, including overall survival (OS) (HR: 1.697, 95% confidence interval [CI]: 1.373-2.021), especially SNHG5 (the HR of OS is 4.74, 95%CI range from 1.35 to 6.64), progression-free survival (HR: 1.85, 95% CI: 1.25-2.73), tumor, node, metastasis (TNM) stage (OR: 1.696, 95% CI: 1.436-2.005), lymph node metastasis (OR: 2.383, 95% CI: 1.098-5.173), and tumor size (OR: 1363, 95% CI: 1.165-1.595). The OS results were found to be reliable and robust, as indicated by the sensitivity analysis. Additionally, Beeg's test demonstrated the absence of any potential publication bias for each result. CONCLUSION: In liver cancer tissues, most SNHGs are highly expressed, which may signal poor prognosis. SNHG has the potential to be an intriguing predictive marker and a prospective therapeutic target for liver cancer.

Asunto(s)

Biomarcadores de Tumor , Carcinoma Hepatocelular , Neoplasias Hepáticas , ARN Nucleolar Pequeño , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Pronóstico , ARN Nucleolar Pequeño/genética , Biomarcadores de Tumor/genética , ARN Largo no Codificante/genética , Regulación Neoplásica de la Expresión Génica

RESUMEN

Small nucleolar RNAs (snoRNAs) were previously regarded as a class of functionally conserved housekeeping genes, primarily involved in the regulation of ribosome biogenesis by ribosomal RNA (rRNA) modification. However, some of them are involved in several biological processes via complex molecular mechanisms. DNA damage response (DDR) is a conserved mechanism for maintaining genomic stability to prevent the occurrence of various human diseases. It has recently been revealed that snoRNAs are involved in DDR at multiple levels, indicating their relevant theoretical and clinical significance in this field. The present review systematically addresses four main points, including the biosynthesis and classification of snoRNAs, the mechanisms through which snoRNAs regulate target molecules, snoRNAs in the process of DDR, and the significance of snoRNA in disease diagnosis and treatment. It focuses on the potential functions of snoRNAs in DDR to help in the discovery of the roles of snoRNAs in maintaining genome stability and pathological processes.

Asunto(s)

Daño del ADN , ARN Nucleolar Pequeño , ARN Nucleolar Pequeño/genética , Daño del ADN/fisiología , Humanos , Inestabilidad Genómica

RESUMEN

Whether small nucleolar RNAs (snoRNAs) are involved in the regulation of liver cancer stem cells (CSCs) self-renewal and serve as therapeutic targets remains largely unclear. Here we show that a functional snoRNA (SNORD88B) is robustly expressed in Hepatocellular carcinoma (HCC) tumors and liver CSCs. SNORD88B deficiency abolishes the self-renewal of liver CSCs and hepatocarcinogenesis. Mechanistically, SNORD88B anchors WRN in the nucleolus, promoting XRCC5 interacts with STK4 promoter to suppress its transcription, leading to inactivation of Hippo signaling. Moreover, low expression of STK4 and high expression of XRCC5 are positively correlated with HCC poor prognosis. Additionally, snord88b knockout suppresses mouse liver tumorigenesis. Notably, co-administration of SNORD88B antisense oligonucleotides (ASOs) with MST1 agonist adapalene (ADA) exert synergistic antitumor effects and increase overall murine survival. Our findings delineate that SNORD88B drives self-renewal of liver CSCs and accelerates HCC tumorigenesis via non-canonical mechanism, providing potential targets for liver cancer therapy by eliminating liver CSCs.

Asunto(s)

Carcinogénesis , Carcinoma Hepatocelular , Neoplasias Hepáticas , Células Madre Neoplásicas , ARN Nucleolar Pequeño , Animales , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Humanos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Ratones , ARN Nucleolar Pequeño/metabolismo , ARN Nucleolar Pequeño/genética , Carcinogénesis/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Helicasa del Síndrome de Werner/metabolismo , Helicasa del Síndrome de Werner/genética , Nucléolo Celular/metabolismo , Línea Celular Tumoral , Autorrenovación de las Células , Regulación Neoplásica de la Expresión Génica , Masculino , Vía de Señalización Hippo , Oligonucleótidos Antisentido/farmacología , Transducción de Señal

RESUMEN

OBJECTIVE: The objective of this study was to conduct an integrative review, addressing the key findings, biological functions, and clinical significance of these biomolecules in solid tumors. METHODS: This document analyzes the main data on the involvement of snoRNAs in solid tumors. For this, Pubmed and Science direct were used, with keywords. Additionally, a search for the host gene was conducted using the snoDB tool, and its chromosomal location was identified using the Hugo Gene Nomenclature Committee (HGNC). RESULTS: According to research conducted in the literature, the majority of snoRNAs were found to be overexpressed and described as regulators of processes such as invasion, cellular proliferation, apoptosis, and migration. They are associated with clinical prognostic factors such as metastasis and worse survival. CONCLUSION: Therefore, it is essential to expand the investigation of snoRNAs in oncology across different types of tumors. The utilization of these biomolecules may pave the way for innovative clinical applications, such as their use in the early detection of neoplasms in non-invasive samples and as therapeutic targets. Broadening research on snoRNAs across various tumor types is crucial.

Asunto(s)

Biomarcadores de Tumor , Neoplasias , ARN Nucleolar Pequeño , Humanos , ARN Nucleolar Pequeño/genética , Neoplasias/genética , Neoplasias/patología , Biomarcadores de Tumor/genética , Pronóstico

RESUMEN

In a recent study in Cell, Cheng and Wang et al.1 show that the small nucleolar RNA (snoRNA) SNORA13 has a non-canonical role in ribosome biogenesis and senescence by acting directly on RPL23 and regulating its assembly into the 60S ribosomal subunit.

Asunto(s)

ARN Nucleolar Pequeño , Proteínas Ribosómicas , Ribosomas , ARN Nucleolar Pequeño/metabolismo , ARN Nucleolar Pequeño/genética , Ribosomas/metabolismo , Ribosomas/genética , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Humanos , Subunidades Ribosómicas Grandes de Eucariotas/metabolismo , Subunidades Ribosómicas Grandes de Eucariotas/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo

RESUMEN

Cellular senescence is an irreversible state of cell-cycle arrest induced by various stresses, including aberrant oncogene activation, telomere shortening, and DNA damage. Through a genome-wide screen, we discovered a conserved small nucleolar RNA (snoRNA), SNORA13, that is required for multiple forms of senescence in human cells and mice. Although SNORA13 guides the pseudouridylation of a conserved nucleotide in the ribosomal decoding center, loss of this snoRNA minimally impacts translation. Instead, we found that SNORA13 negatively regulates ribosome biogenesis. Senescence-inducing stress perturbs ribosome biogenesis, resulting in the accumulation of free ribosomal proteins (RPs) that trigger p53 activation. SNORA13 interacts directly with RPL23, decreasing its incorporation into maturing 60S subunits and, consequently, increasing the pool of free RPs, thereby promoting p53-mediated senescence. Thus, SNORA13 regulates ribosome biogenesis and the p53 pathway through a non-canonical mechanism distinct from its role in guiding RNA modification. These findings expand our understanding of snoRNA functions and their roles in cellular signaling.

Asunto(s)

Senescencia Celular , ARN Nucleolar Pequeño , Proteínas Ribosómicas , Ribosomas , Proteína p53 Supresora de Tumor , Humanos , ARN Nucleolar Pequeño/metabolismo , ARN Nucleolar Pequeño/genética , Senescencia Celular/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Ribosomas/metabolismo , Animales , Ratones , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética

RESUMEN

A fundamental challenge in molecular biology is to understand how evolving genomes can acquire new functions. Actively transcribed, non-coding parts of the genome provide a potential platform for the development of new functional sequences, but their biological and evolutionary roles remain largely unexplored. Here, we show that a set of neutrally evolving long non-coding RNAs (lncRNAs) whose introns encode small nucleolar RNAs (snoRNA Host Genes, SNHGs) are highly expressed in skin and dysregulated in inflammatory conditions. Using SNHG7 and human epidermal keratinocytes as a model, we describe a mechanism by which these lncRNAs can increase self-renewal and inhibit differentiation. The activity of SNHG7 lncRNA has been recently acquired in the primate lineage and depends on a short sequence required for microRNA binding. Taken together, our results highlight the importance of understanding the role of fast-evolving transcripts in normal and diseased epithelia, and show how poorly conserved, actively transcribed non-coding sequences can participate in the evolution of genomic functionality.

Asunto(s)

Diferenciación Celular , Evolución Molecular , Queratinocitos , ARN Largo no Codificante , ARN Nucleolar Pequeño , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Humanos , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Animales , Queratinocitos/metabolismo , Diferenciación Celular/genética , MicroARNs/genética , MicroARNs/metabolismo

RESUMEN

Small nucleolar RNAs (snoRNAs) are earning increasing attention from research communities due to their critical role in the post-transcriptional modification of various RNAs. These snoRNAs, along with their associated proteins, are crucial in regulating the expression of a vast array of genes in different human diseases. Primarily, snoRNAs facilitate modifications such as 2'-O-methylation, N-4-acetylation, and pseudouridylation, which impact not only ribosomal RNA (rRNA) and their synthesis but also different RNAs. Functionally, snoRNAs bind with core proteins to form small nucleolar ribonucleoproteins (snoRNPs). These snoRNAs then direct the protein complex to specific sites on target RNA molecules where modifications are necessary for either standard cellular operations or the regulation of pathological mechanisms. At these targeted sites, the proteins coupled with snoRNPs perform the modification processes that are vital for controlling cellular functions. The unique characteristics of snoRNAs and their involvement in various non-metabolic and metabolic diseases highlight their potential as therapeutic targets. Moreover, the precise targeting capability of snoRNAs might be harnessed as a molecular tool to therapeutically address various disease conditions. This review delves into the role of snoRNAs in health and disease and explores the broad potential of these snoRNAs as therapeutic agents in human pathologies.

Asunto(s)

ARN Nucleolar Pequeño , Ribonucleoproteínas Nucleolares Pequeñas , Humanos , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Ribonucleoproteínas Nucleolares Pequeñas/metabolismo , Ribonucleoproteínas Nucleolares Pequeñas/genética , Animales , Procesamiento Postranscripcional del ARN , Neoplasias/genética , Neoplasias/metabolismo

RESUMEN

The development of high-throughput technologies has enhanced our understanding of small non-coding RNAs (sncRNAs) and their crucial roles in various diseases, including atrial fibrillation (AF). This study aimed to systematically delineate sncRNA profiles in AF patients. PANDORA-sequencing was used to examine the sncRNA profiles of atrial appendage tissues from AF and non-AF patients. Differentially expressed sncRNAs were identified using the R package DEGseq 2 with a fold change >2 and p < 0.05. The target genes of the differentially expressed sncRNAs were predicted using MiRanda and RNAhybrid. Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. In AF patients, the most abundant sncRNAs were ribosomal RNA-derived small RNAs (rsRNAs), followed by transfer RNA-derived small RNAs (tsRNAs), and microRNAs (miRNAs). Compared with non-AF patients, 656 rsRNAs, 45 miRNAs, 191 tsRNAs and 51 small nucleolar RNAs (snoRNAs) were differentially expressed in AF patients, whereas no significantly differentially expressed piwi-interacting RNAs were identified. Two out of three tsRNAs were confirmed to be upregulated in AF patients by quantitative reverse transcriptase polymerase chain reaction, and higher plasma levels of tsRNA 5006c-LysCTT were associated with a 2.55-fold increased risk of all-cause death in AF patients (hazard ratio: 2.55; 95% confidence interval, 1.56-4.17; p < 0.001). Combined with our previous transcriptome sequencing results, 32 miRNA, 31 snoRNA, 110 nucleus-encoded tsRNA, and 33 mitochondria-encoded tsRNA target genes were dysregulated in AF patients. GO and KEGG analyses revealed enrichment of differentially expressed sncRNA target genes in AF-related pathways, including the 'calcium signaling pathway' and 'adrenergic signaling in cardiomyocytes.' The dysregulated sncRNA profiles in AF patients suggest their potential regulatory roles in AF pathogenesis. Further research is needed to investigate the specific mechanisms of sncRNAs in the development of AF and to explore potential biomarkers for AF treatment and prognosis.

Asunto(s)

Apéndice Atrial , Fibrilación Atrial , Perfilación de la Expresión Génica , ARN Pequeño no Traducido , Humanos , Fibrilación Atrial/genética , ARN Pequeño no Traducido/genética , Apéndice Atrial/metabolismo , Masculino , Femenino , MicroARNs/genética , Ontología de Genes , Anciano , Persona de Mediana Edad , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Regulación de la Expresión Génica , Transcriptoma/genética , Biología Computacional/métodos , Pronóstico

RESUMEN

In cell biology, ribosomal RNA (rRNA) 2'O-methyl (2'-O-Me) is the most prevalent posttranscriptional chemical modification contributing to ribosome heterogeneity. The modification involves a family of small nucleolar RNAs (snoRNAs) and is specified by box C/D snoRNAs (SNORDs). Given the importance of ribosome biogenesis for skeletal muscle growth, we asked if rRNA 2'-O-Me in nascent ribosomes synthesized in response to a growth stimulus is an unrecognized mode of ribosome heterogeneity in muscle. To determine the pattern and dynamics of 2'-O-Me rRNA, we used a sequencing-based profiling method called RiboMeth-seq (RMS). We applied this method to tissue-derived rRNA of skeletal muscle and rRNA specifically from the muscle fiber using an inducible myofiber-specific RiboTag mouse in sedentary and mechanically overloaded conditions. These analyses were complemented by myonuclear-specific small RNA sequencing to profile SNORDs and link the rRNA epitranscriptome to known regulatory elements generated within the muscle fiber. We demonstrate for the first time that mechanical overload of skeletal muscle 1) induces decreased 2'-O-Me at a subset of skeletal muscle rRNA and 2) alters the SNORD profile in isolated myonuclei. These findings point to a transient diversification of the ribosome pool via 2'-O-Me during growth and adaptation in skeletal muscle. These findings suggest changes in ribosome heterogeneity at the 2'-O-Me level during muscle hypertrophy and lay the foundation for studies investigating the functional implications of these newly identified "growth-induced" ribosomes.NEW & NOTEWORTHY Ribosomal RNAs (rRNAs) are posttranscriptionally modified by 2'O-methyl (2'-O-Me). This study applied RiboMeth-seq (RMS) to detect changes in 2'-O-Me levels during skeletal muscle hypertrophy, uncovering transient diversification of the ribosome pool in skeletal muscle fibers. This work implies a role for ribosome heterogeneity in skeletal muscle growth and adaptation.

Asunto(s)

Fibras Musculares Esqueléticas , ARN Ribosómico , ARN Nucleolar Pequeño , Ribosomas , Transcriptoma , Animales , Ribosomas/metabolismo , Ribosomas/genética , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , Ratones , Fibras Musculares Esqueléticas/metabolismo , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Hipertrofia/genética , Masculino , Ratones Endogámicos C57BL , Procesamiento Postranscripcional del ARN , Músculo Esquelético/metabolismo , Epigénesis Genética

RESUMEN

Radiotherapy is essential for treating colorectal cancer (CRC), especially in advanced rectal cancer. However, the low radiosensitivity of CRC cells greatly limits radiotherapy efficacy. Small nucleolar RNAs (snoRNAs) are a class of noncoding RNA that primarily direct post-transcriptional modifications of ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and other cellular RNAs. While snoRNAs are involved in tumor progression and chemoresistance, their association with radiosensitivity remains largely unknown. Herein, SNORA28 is shown highly expressed in CRC and is positively associated with poor prognosis. Furthermore, SNORA28 overexpression enhances the growth and radioresistance of CRC cells in vitro and in vivo. Mechanistically, SNORA28 acts as a molecular decoy that recruits bromodomain-containing protein 4 (BRD4), which increases the level of H3K9 acetylation at the LIFR promoter region. This stimulates LIFR transcription, which in turn triggers the JAK1/STAT3 pathway, enhancing the proliferation and radioresistance of CRC cells. Overall, these results highlight the ability of snoRNAs to regulate radiosensitivity in tumor cells and affect histone acetylation modification in the promoter region of target genes, thus broadening the current knowledge of snoRNA biological functions and the mechanism underlying target gene regulation.

Asunto(s)

Proliferación Celular , Neoplasias Colorrectales , ARN Nucleolar Pequeño , Tolerancia a Radiación , Factor de Transcripción STAT3 , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/radioterapia , Proliferación Celular/genética , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Tolerancia a Radiación/genética , Acetilación , Ratones , Línea Celular Tumoral , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Animales , Regiones Promotoras Genéticas/genética , Regulación Neoplásica de la Expresión Génica/genética , Histonas/metabolismo , Histonas/genética , Ratones Desnudos , Transducción de Señal/genética , Modelos Animales de Enfermedad

RESUMEN

The factors driving glioma progression remain poorly understood. Here, the epigenetic regulator TRIM24 is identified as a driver of glioma progression, where TRIM24 overexpression promotes HRasV12 anaplastic astrocytoma (AA) progression into epithelioid GBM (Ep-GBM)-like tumors. Co-transfection of TRIM24 with HRasV12 also induces Ep-GBM-like transformation of human neural stem cells (hNSCs) with tumor protein p53 gene (TP53) knockdown. Furthermore, TRIM24 is highly expressed in clinical Ep-GBM specimens. Using single-cell RNA-sequencing (scRNA-Seq), the authors show that TRIM24 overexpression impacts both intratumoral heterogeneity and the tumor microenvironment. Mechanically, HRasV12 activates phosphorylated adaptor for RNA export (PHAX) and upregulates U3 small nucleolar RNAs (U3 snoRNAs) to recruit Ku-dependent DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Overexpressed TRIM24 is also recruited by PHAX to U3 snoRNAs, thereby facilitating DNA-PKcs phosphorylation of TRIM24 at S767/768 residues. Phosphorylated TRIM24 induces epigenome and transcription factor network reprogramming and promotes Ep-GBM-like transformation. Targeting DNA-PKcs with the small molecule inhibitor NU7441 synergizes with temozolomide to reduce Ep-GBM tumorigenicity and prolong animal survival. These findings provide new insights into the epigenetic regulation of Ep-GBM-like transformation and suggest a potential therapeutic strategy for patients with Ep-GBM.

Asunto(s)

Progresión de la Enfermedad , Glioma , Mutación , ARN Nucleolar Pequeño , Animales , Humanos , Ratones , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Proteínas Portadoras , Línea Celular Tumoral , Modelos Animales de Enfermedad , Proteína Quinasa Activada por ADN/genética , Proteína Quinasa Activada por ADN/metabolismo , Glioma/genética , Glioma/metabolismo , Glioma/patología , Mutación/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas ras/metabolismo , Proteínas ras/genética , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo

RESUMEN

The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116, SNORD115, and SNORD109A, as well as protein-coding genes MKRN3 and SNRPN, thus bridging the gap between PWS and SYS.

Asunto(s)

Péptidos y Proteínas de Señalización Intracelular , Proteínas Intrínsecamente Desordenadas , Síndrome de Prader-Willi , Humanos , Cromosomas Humanos Par 15/genética , Citoplasma/metabolismo , Células HEK293 , Mutación , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Síndrome de Prader-Willi/genética , Proteínas/genética , Proteínas/metabolismo , ARN Nucleolar Pequeño/genética

RESUMEN

RNA constitutes a large fraction of chromatin. Spatial distribution and functional relevance of most of RNA-chromatin interactions remain unknown. We established a landscape analysis of RNA-chromatin interactions in human acute myeloid leukemia (AML). In total more than 50 million interactions were captured in an AML cell line. Protein-coding mRNAs and long non-coding RNAs exhibited a substantial number of interactions with chromatin in cis suggesting transcriptional activity. In contrast, small nucleolar RNAs (snoRNAs) and small nuclear RNAs (snRNAs) associated with chromatin predominantly in trans suggesting chromatin specific functions. Of note, snoRNA-chromatin interaction was associated with chromatin modifications and occurred independently of the classical snoRNA-RNP complex. Two C/D box snoRNAs, namely SNORD118 and SNORD3A, displayed high frequency of trans-association with chromatin. The transcription of SNORD118 and SNORD3A was increased upon leukemia transformation and enriched in leukemia stem cells, but decreased during myeloid differentiation. Suppression of SNORD118 and SNORD3A impaired leukemia cell proliferation and colony forming capacity in AML cell lines and primary patient samples. Notably, this effect was leukemia specific with less impact on healthy CD34+ hematopoietic stem and progenitor cells. These findings highlight the functional importance of chromatin-associated RNAs overall and in particular of SNORD118 and SNORD3A in maintaining leukemia propagation.

Asunto(s)

Cromatina , Leucemia Mieloide Aguda , Humanos , Cromatina/metabolismo , Cromatina/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , ARN Pequeño no Traducido/genética , Proliferación Celular/genética , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Línea Celular Tumoral

RESUMEN

A number of patients with colon cancer with local or local advanced disease suffer from recurrence and there is an urgent need for better prognostic biomarkers in this setting. Here, the transcriptomic landscape of mRNAs, long noncoding RNAs, snRNAs, small nucleolar RNAs (snoRNAs), small Cajal body-specific RNAs, pseudogenes, and circular RNAs, as well as RNAs denoted as miscellaneous RNAs, was profiled by total RNA sequencing. In addition to well-known coding and noncoding RNAs, differential expression analysis also uncovered transcripts that have not been implicated previously in colon cancer, such as RNA5SP149, RNU4-2, and SNORD3A. Moreover, there was a profound global up-regulation of snRNA pseudogenes, snoRNAs, and rRNA pseudogenes in more advanced tumors. A global down-regulation of circular RNAs in tumors relative to normal tissues was observed, although only a few were expressed differentially between tumor stages. Many previously undescribed transcripts, including RNU6-620P, RNU2-20P, VTRNA1-3, and RNA5SP60, indicated strong prognostic biomarker potential in receiver operating characteristics analyses. In summary, this study unveiled numerous differentially expressed RNAs across various classes between recurrent and nonrecurrent colon cancer. Notably, there was a significant global up-regulation of snRNA pseudogenes, snoRNAs, and rRNA pseudogenes in advanced tumors. Many of these newly discovered candidates demonstrate a strong prognostic potential for stage II colon cancer.

Asunto(s)

Neoplasias del Colon , Regulación Neoplásica de la Expresión Génica , Recurrencia Local de Neoplasia , Humanos , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/metabolismo , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , ARN no Traducido/genética , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Transcriptoma/genética , Masculino , Perfilación de la Expresión Génica/métodos , Femenino

RESUMEN

U3 snoRNA is essential for ribosome biogenesis during interphase. Upon mitotic onset, the nucleolus disassembles and U3 snoRNA relocates to the perichromosomal region (PR) to be considered as a chromosome passenger. Whether U3 controls mitosis remains unknown. Here, we demonstrate that U3 snoRNA is required for mitotic progression. We identified DDX21 as the predominant U3-binding protein during mitosis and confirmed that U3 snoRNA colocalizes with DDX21 in the PR. DDX21 knockdown induces mitotic catastrophe and similar mitotic defects caused by U3 snoRNA depletion. Interestingly, the uniform PR distribution of U3 snoRNA and DDX21 is interdependent. DDX21 functions in mitosis depending on its PR localization. Mechanistically, U3 snoRNA regulates DDX21 PR localization through maintaining its mobility. Moreover, Cy5-U3 snoRNA downsizes the fibrous condensates of His-DDX21 at proper molecular ratios in vitro. This work highlights the importance of the equilibrium between U3 snoRNA and DDX21 in PR formation and reveals the potential relationship between the PR assembly and mitotic regulation.

Asunto(s)

ARN Helicasas DEAD-box , Mitosis , ARN Nucleolar Pequeño , Humanos , ARN Helicasas DEAD-box/metabolismo , ARN Helicasas DEAD-box/genética , Células HeLa , ARN Nucleolar Pequeño/metabolismo , ARN Nucleolar Pequeño/genética , Cromosomas/metabolismo

RESUMEN

Ribosomal RNAs (rRNAs) are extensively modified during the transcription and subsequent maturation. Three types of modifications, 2'-O-methylation of ribose moiety, pseudouridylation, and base modifications, are introduced either by a snoRNA-driven mechanism or by stand-alone enzymes. Modified nucleotides are clustered at the functionally important sites, including peptidyl transferase center (PTC). Therefore, it has been hypothesised that the modified nucleotides play an important role in ensuring the functionality of the ribosome. In this study, we demonstrate that seven 25S rRNA modifications, including four evolutionarily conserved modifications, in the proximity of PTC can be simultaneously depleted without loss of cell viability. Yeast mutants lacking three snoRNA genes (snR34, snR52, and snR65) and/or expressing enzymatically inactive variants of spb1(D52A/E679K) and nop2(C424A/C478A) were constructed. The results show that rRNA modifications in PTC contribute collectively to efficient translation in eukaryotic cells. The deficiency of seven modified nucleotides in 25S rRNA resulted in reduced cell growth, cold sensitivity, decreased translation levels, and hyperaccurate translation, as indicated by the reduced missense and nonsense suppression. The modification m5C2870 is crucial in the absence of the other six modified nucleotides. Thus, the pattern of rRNA-modified nucleotides around the PTC is essential for optimal ribosomal translational activity and translational fidelity.

Asunto(s)

Peptidil Transferasas , Biosíntesis de Proteínas , ARN Ribosómico , Saccharomyces cerevisiae , ARN Ribosómico/genética , ARN Ribosómico/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Peptidil Transferasas/metabolismo , Peptidil Transferasas/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomycetales/genética , Saccharomycetales/metabolismo , Ribosomas/metabolismo , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Procesamiento Postranscripcional del ARN , ARN de Hongos/genética , ARN de Hongos/metabolismo , Mutación

RESUMEN

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC with high rates of metastasis. Targeted therapies such as tyrosine kinase and checkpoint inhibitors have improved treatment success, but therapy-related side effects and tumor recurrence remain a challenge. As a result, ccRCC still have a high mortality rate. Early detection before metastasis has great potential to improve outcomes, but no suitable biomarker specific for ccRCC is available so far. Therefore, molecular biomarkers derived from body fluids have been investigated over the past decade. Among them, RNAs from urine-derived extracellular vesicles (EVs) are very promising. METHODS: RNA was extracted from urine-derived EVs from a cohort of 78 subjects (54 ccRCC patients, 24 urolithiasis controls). RNA-seq was performed on the discovery cohort, a subset of the whole cohort (47 ccRCC, 16 urolithiasis). Reads were then mapped to the genome, and expression was quantified based on 100 nt long contiguous genomic regions. Cluster analysis and differential region expression analysis were performed with adjustment for age and gender. The candidate biomarkers were validated by qPCR in the entire cohort. Receiver operating characteristic, area under the curve and odds ratios were used to evaluate the diagnostic potential of the models. RESULTS: An initial cluster analysis of RNA-seq expression data showed separation by the subjects' gender, but not by tumor status. Therefore, the following analyses were done, adjusting for gender and age. The regions differentially expressed between ccRCC and urolithiasis patients mainly overlapped with small nucleolar RNAs (snoRNAs). The differential expression of four snoRNAs (SNORD99, SNORD22, SNORD26, SNORA50C) was validated by quantitative PCR. Confounder-adjusted regression models were then used to classify the validation cohort into ccRCC and tumor-free subjects. Corresponding accuracies ranged from 0.654 to 0.744. Models combining multiple genes and the risk factors obesity and hypertension showed improved diagnostic performance with an accuracy of up to 0.811 for SNORD99 and SNORA50C (p = 0.0091). CONCLUSIONS: Our study uncovered four previously unrecognized snoRNA biomarkers from urine-derived EVs, advancing the search for a robust, easy-to-use ccRCC screening method.

Asunto(s)

Biomarcadores de Tumor , Carcinoma de Células Renales , Vesículas Extracelulares , Neoplasias Renales , ARN Nucleolar Pequeño , Humanos , Carcinoma de Células Renales/orina , Carcinoma de Células Renales/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Biomarcadores de Tumor/orina , Biomarcadores de Tumor/genética , Femenino , Masculino , Persona de Mediana Edad , Neoplasias Renales/orina , Neoplasias Renales/genética , Anciano , ARN Nucleolar Pequeño/genética , Estudios de Cohortes , Adulto

RESUMEN

More and more evidence shows that small noncoding RNAs (ncRNAs) play diverse roles in development, stress response and other cellular processes, but functional study of intermediate-size ncRNAs is still rare. Here, the expression profile of 16 intermediate-size ncRNAs in ovary and testis of silkworm Bombyx mori were analyzed. Twelve ncRNAs, including 5 small nucleolar RNAs (snoRNAs) and 7 unclassified ncRNAs, accumulated more in the testis than in the ovary of silkworm, especially Bm-163, Bm-51 and Bm-68. Four ncRNAs (including three orphan snoRNAs and one unclassified ncRNA) had higher expression level in the ovary than in the testis, especially Bm-86. Overexpression of the testis-enriched snoRNA Bm-68 in the female led to the accumulation of male-specific isoform of doublesex (BmdsxM) and increased the expression ratio of BmdsxM: BmdsxF. While overexpression of ovary-enriched snoRNA Bm-86 in the male decreased the expression ratio of BmdsxM: BmdsxF, indicating the roles of the two snoRNAs played in the alternative splicing of Bmdsx of silkworm, which will provide new clues for the functional study of snoRNAs in insects.

Asunto(s)

Empalme Alternativo , Bombyx , Proteínas de Unión al ADN , Proteínas de Insectos , ARN Nucleolar Pequeño , Animales , Femenino , Masculino , Bombyx/genética , Bombyx/metabolismo , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Ovario/metabolismo , ARN Nucleolar Pequeño/genética , ARN Nucleolar Pequeño/metabolismo , Testículo/metabolismo

RESUMEN

OBJECTIVES: Small nucleolar RNAs (snoRNAs) form clusters within the genome, representing a mysterious category of small non-coding RNAs. Research has demonstrated that aberrant snoRNAs can contribute to the development of various types of cancers. Recent studies have identified snoRNAs as potentially valuable biomarkers for the diagnosis or/and prognosis of cancers. However, there has been a lack of comprehensive reviews on prognostic and diagnostic snoRNAs across different types of cancers. METHODS: We conducted a systematic search of various databases including Google Scholar, Medline, Cochrane, Scopus, PubMed, Embase, ScienceDirect, Ovid-Medline, Chinese National Knowledge Infrastructure, WanFang, and SinoMed with a time frame reception to December 30, 2022. A total of 49 relevant articles were included in our analysis, consisting of 21 articles focusing on diagnostic aspects and 41 articles focusing on prognostic aspects. Pooled odds ratio, 95% confidence intervals (CIs), and hazard ratio (HR) were utilized to evaluate clinical parameters and overall survival (OS), respectively. RESULT: The findings indicated that area under the curve, sensitivity, and specificity were 0.85, 75%, and 80% in cancer, respectively. There was a possibility that snoRNAs had a positive impact on the diagnosis (risk ratio, RR = 2.95, 95% CI: 2.75-3.16, P = 0.000) and OS (HR = 1) in cancer. Additionally, abnormally expressed snoRNAs were associated with a positive impact on OS time for chronic lymphocytic leukemia (HR: 0.88, 95%Cl: 0.69-1.11, P < 0.00001), colon adenocarcinoma (HR: 0.97, 95%Cl: 0.91-1.03, P < 0.0001), and ovarian cancer (HR: 0.98, 95%Cl: 0.98-0.99, P < 0.00001). However, dysregulated snoRNAs of colon cancer and colorectal cancer had a negative impact on OS time (HR = 3.01 and 1.01 respectively, P < 0.0001). CONCLUSION: The results strongly suggested that snoRNAs could serve as potential novel indicators for prognosis and diagnosis in cancers. This systematic review followed the guidelines of the Transparent Reporting of Systematic Review and Meta-Analyses (PROSPERO register: CRD42020209096).

Asunto(s)

Biomarcadores de Tumor , Neoplasias , ARN Nucleolar Pequeño , Humanos , ARN Nucleolar Pequeño/genética , Biomarcadores de Tumor/genética , Pronóstico , Neoplasias/genética , Neoplasias/diagnóstico , Neoplasias/mortalidad , Curva ROC