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PubMed2025

Role of lncRNA PVT1 in the progression of urological cancers: Novel insights into signaling pathways and clinical opportunities.

Urologic malignancies, encompassing cancers of the kidney, bladder, and prostate, represent approximately 25 % of all cancer cases. Recent advances have enhanced our understanding of PVT1's crucial functions. Long noncoding RNAs influence both the onset and development of cancer, as well as epigenetic alterations. Recent findings have focused on PVT1's mechanism of action across several malignancies, particularly urologic cancers. Understanding the various functions of PVT1 linked to cancer is necessary for the development of cancer detection and treatment when PVT1 is dysregulated. Furthermore, recent advancements in genomic and epigenetic research have elucidated the complex regulatory networks that control PVT1 expression. Comprehending the intricate role of PVT1 Understanding the complex function of PVT1 in urologic cancers has substantial clinical implications. Here, we summarize some of the most recent findings about the carcinogenic effects of PVT1 signaling pathways and the possible treatment strategies for urological malignancies that target these pathways.

Humans↗

PubMed2025

Comprehensive circRNA expression profile and hub genes screening during human liver development.

BACKGROUND: Understanding the expression of non-coding RNA in the liver during embryonic development provides important insights into liver diseases. Therefore, we investigated circular RNA (circRNA) roles in human liver development, an unexplored research domain. METHODS: Using high-throughput sequencing and bioinformatics, we analysed foetal liver samples across developmental stages (7-20 weeks post-conception). Differentially expressed (DE) genes were identified and subjected to enrichment analysis using Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes (KEGG), and Disease Ontology (DO). Modular analysis was performed using the Search Tool for Retrieval of Interacting Genes (STRING), followed by construction of a protein-protein interaction (PPI) network using Cytoscape software. The key genes were screened using Molecular Complex Detection (MCODE). The mRNA levels of hub genes were validated using quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: There were 645 DE circRNAs and 5,145 DE mRNAs between human livers at the three growth stages (HB, EH, and LH). It was found that the activity of circRNAs was boosted remarkably in the hepatoblastic stage. Enrichment analysis found they mainly involved in nervous system regulation of liver function, embryonic organ development and digestive system development. In addition, DE circRNAs were primarily involved in the PI3K-AKT, MAPK and calcium pathways, potentially contributing to adult liver diseases. Notably, only hsa_circ_001471 and novel_circ_017382 were simultaneously identified at all stages and were persistently downregulated. A co-expression regulatory network involving these circRNAs was established. Three hub genes (LGR5, FOXL1 and RSPO3) were identified from the PPI network of 167 genes and may play key roles in human liver development. The RT-qPCR validation results were in agreement with the sequencing data. CONCLUSIONS: Our findings provide the first insights into the roles and regulatory networks of circRNAs in human liver development, laying the groundwork for further investigations of molecular and signalling networks.

Humans↗

PubMed1990

The complete and symmetric transcription of the main non coding region of rat mitochondrial genome: in vivo mapping of heavy and light transcripts.

The experiments here reported demonstrate that the main non-coding region of rat mitochondrial DNA is symmetrically transcribed. We have identified stable heavy and light transcripts, whose pattern is rather complex, in the D-loop region of rat mitochondrial DNA. Their relative concentrations have been determined. We detected heavy transcripts which encompass the whole D-loop and more abundant heavy RNA species which we interpreted as transcripts terminating downstream of the 3' end of the last coded gene (Thr-tRNA). The processed heavy RNA species contain polyA, suggesting a strict association between cleavage and polyadenylation. The pattern of light transcripts shows a long RNA, which, starting from the light strand promoter, covers the whole segment, and shorter RNA species which seems to be actively processed at the level of the conserved sequence boxes, probably acting as primers. The symmetric transcription of the D-loop containing region of rat mitochondrial DNA, and in particular the presence of stable transcripts complementary to the putative RNA primers, suggest that mechanisms mediated by interaction between complementary transcripts (antisense RNAs) might play a role in the regulation of mitochondrial DNA replication and expression.

Amino Acid Sequence↗

PubMed1984

Complete nucleotide sequences of all three poliovirus serotype genomes. Implication for genetic relationship, gene function and antigenic determinants.

The complete nucleotide sequences of the genomes of the type 2 ( P712 , Ch, 2ab ) and type 3 (Leon 12a1b ) poliovirus vaccine strains were determined. Comparison of the sequences with the previously established genome sequence of type 1 (LS-c, 2ab ) poliovirus vaccine strain revealed that 71% of the nucleotides in the genome RNAs were common, that the 5' and 3' termini of the genomes were highly homologous, and that more than 80% of the nucleotide differences in the coding region occurred in the third letter position of in-phase codons, resulting in a low frequency of amino acid difference. These results strongly suggested that the serotypes of poliovirus derived from a common prototype. A comparison of the amino acid sequences predicted from the genome sequences showed highest variation in the capsid protein region, whereas non-structural proteins are highly conserved. Initiation of polyprotein synthesis occurs in all three strains more than 740 nucleotides downstream from the 5' end. An analysis of the non-coding region suggests that small peptides that could potentially originate from this region are conserved. The amino acid sequences immediately surrounding the cleavage signals, however, show a higher than average degree of variation. The analysis of the amino acid sequences of the capsid protein VP1 of all serotypes has led to the prediction of potential antigenic sites on the virion involved in neutralization.

Amino Acid Sequence↗

PubMed1984

Identification of two types of keratin polypeptides within the acidic cytokeratin subfamily I.

Cytoskeletal filaments of the alpha-keratin type (cytokeratins) are a characteristic of epithelial cells. In diverse mammals (man, cow and rodents) these cytokeratins consist of a family of approximately 20 polypeptides, which may be divided into the more acidic (I) and the more basic (II) subfamilies. These two subfamilies show only limited amino acid sequence homology. In contrast, nucleic acid hybridization experiments and peptide maps have been interpreted to show that polypeptides of the same subfamily share extended sequence homology. We compare two polypeptides of the acidic cytokeratin subfamily, VIb (Mr 54,000) and VII (Mr 50,000), which are co-expressed in large amounts in bovine epidermal keratinocytes. These two epidermal keratins can be distinguished by specific antibodies and show different patterns of expression among several bovine tissues and cultured cells. In addition, they differ in the stability of their complexes with basic keratin polypeptides and in their tryptic peptide maps. The amino acid sequences deduced from the nucleotide sequences of complementary DNA clones containing the 3' ends of the messenger RNAs for these keratins are compared with each other and with available amino acid sequences of human, murine and amphibian epidermal keratins. Bovine keratins VIb and VII share considerable sequence homology in the alpha-helical portion (68% residues identical) but lack significant homology in the extrahelical portion. Bovine keratin VIb shows, in its alpha-helical region, a pronounced sequence homology (88% identity) to the murine epidermal keratin of Mr 59,000. In addition, the non-helical carboxy-terminal regions of both proteins are glycine-rich and contain a canonic sequence GGGSGYGG, which may be repeated several times. Moreover, their mRNAs present a highly conserved stretch of 236 nucleotides containing, in the murine sequence, the end of the coding and all of the non-coding region (81% identical nucleotides). Bovine keratin VII is considerably different from the murine Mr 59,000 keratin but is almost identical to the human cytokeratin number 14 of Mr 50,000, both in the alpha-helical and in the non-alpha-helical regions of the proteins, and the mRNAs of the human and the bovine keratins also display a high homology in their 3' non-coding ends. The results show that in the same species keratins of the same subfamily can differ considerably, whereas equivalent keratin polypeptides of different species are readily identified by characteristic sequence homologies in the alpha-helical and the non-helical regions as well as in the 3' non-coding portions of their mRNAs.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1986

Transcription initiation of the Saccharomyces cerevisiae iso-1-cytochrome c gene. Multiple, independent T-A-T-A sequences.

The expression of the Saccharomyces cerevisiae CYC1 gene, which encodes iso-1-cytochrome c, produces a family of messenger RNAs whose 5' ends map in the region from position +7 to -93 relative to the first nucleotide at position +1 of the protein-coding DNA sequence. The mechanism of transcription initiation of the CYC1 gene has been examined by using linker-scanning deletions and gene fusions. The various CYC1 derivatives with mutations in the 5' non-coding region were constructed, reintroduced into yeast using a multicopy plasmid, and the mRNA starts mapped by primer extension. The results indicate that four, and possibly five T-A-T-A sequences are located within the 5' non-coding region of the CYC1 gene, and that each T-A-T-A is required for a specific subset of mRNA starts. This conclusion has been confirmed by oligonucleotide mutagenesis of a chromosomal CYC1 T-A-T-A sequence. A loose spatial relationship also exists between the T-A-T-A sequences and the mRNA start sites, and this distance relationship varies from 100 to 60 base-pairs (+/- 15 base-pairs).

Base Sequence↗

PubMed1992

Marburg virus, a filovirus: messenger RNAs, gene order, and regulatory elements of the replication cycle.

The genome of Marburg virus (MBG), a filovirus, is 19.1 kb in length and thus the largest one found with negative-strand RNA viruses. The gene order - 3' untranslated region-NP-VP35-VP40-GP-VP30-VP24-L-5' untranslated region-resembles that of other non-segmented negative-strand (NNS) RNA viruses. Six species of polyadenylated subgenomic RNAs, isolated from MBG-infected cells, are complementary to the negative-strand RNA genome. They can be translated in vitro into the known structural proteins NP, GP (non-glycosylated form), VP40, VP35, VP30 and VP24. At the gene boundaries conserved transcriptional start (3'-NNCUNCNUNUAAUU-5') and stop signals (3'-UAAUUCUUUUU-5') are located containing the highly conserved pentamer 3'-UAAUU-5'. Comparison with other NNS RNA viruses shows conservation primarily in the termination signals, whereas the start signals are more variable. The intergenic regions vary in length and nucleotide composition. All genes have relatively long 3' and 5' end non-coding regions. The putative 3' and 5' leader RNA sequences of the MBG genome resemble those of other NNS RNA viruses in length, conservation at the 3' and 5' ends, and in being complementary at their extremities. The data support the concept of a common taxonomic order Mononegavirales comprising the Filoviridae, Paramyxoviridae, and Rhabdoviridae families.

Base Sequence↗

PubMed1983

Cloning and sequence analysis of a rat liver cDNA coding for a phenobarbital-inducible microheterogenous cytochrome P-450 variant: regulation of its messenger level by xenobiotics.

A rat liver cDNA library was prepared from total polyribosomal poly(A)+ RNA extracted from phenobarbital-treated animals. A cDNA clone coding for a phenobarbital-inducible cytochrome P-450 (PB P-450) was identified by differential colony hybridization to cDNAs synthesized from liver poly(A)+RNAs isolated from phenobarbital-treated rats for positive selection and cDNAs from either untreated rats or beta-naphthoflavone-treated rats as negative controls, followed by hybrid-selected translation and analysis of the translation products by immunoprecipitation. As the cloning and screening strategies involve no prior enrichment for specific mRNAs, they also permit the identification of sequences coding for phenobarbital-induced proteins other than cytochromes P-450. This relatively straightforward approach is generally applicable to the molecular cloning of sequences coding for other inducible cytochromes P-450. Nucleic acid sequencing data indicated that the cloned PB P-450 cDNA codes for a cytochrome P-450 variant [designated P-450e(U.C.)] that is very similar, but not identical, to P-450e. Sequence analysis of the section of cDNA specifying the 3'-non-coding region of the mRNA revealed that it lacked the usual poly(A) addition site signal sequence but contained three inverted repeat structures. Solution hybridization analysis demonstrated that PB P-450 mRNA is increased 20-fold by phenobarbital treatment and decreased 3-fold by beta-naphthoflavone treatment.

Animals↗

PubMed2026

Genome-wide detection of human 5' UTR variants that impact protein translation.

The 5' untranslated region (5' UTR) of messenger RNAs (mRNAs) plays a central role in regulating protein synthesis initiation, particularly through the Kozak sequence and upstream open reading frames (uORFs). Genetic variants within these regulatory elements could affect translation, altering gene expression and contributing to clinical phenotypes in humans. We developed a computational method called 5ULTRA (5' Untranslated Region Annotation) for analysis of whole-exome sequencing and whole-genome sequencing data to detect, annotate, and prioritize 5' UTR variants with potential translation impact. 5ULTRA identifies single-nucleotide variants, indels, and splicing variants that affect uORFs by creating or disrupting start/stop codons and that alter Kozak sequence strength of either the uORFs or the main coding sequence. 5ULTRA incorporates recent uORF databases and provides comprehensive annotations. 5ULTRA implements a machine-learning score to prioritize candidate variants with predicted effects on translation and also provides specific mechanistic predictions. The score correlates strongly with experimentally measured protein-level effects of 5' UTR variants. We applied 5ULTRA to multiple genetics datasets across diverse disease contexts, identifying candidate variants including potential cancer-driving somatic mutations predicted to decrease ABI1 level or increase NRAS abundance; common variants associated with traits such as multiple sclerosis, lung function, and cardiovascular function, by altering protein levels of TAGAP, VRTN, and SPAAR, respectively; and rare germline variants in our cohort, including a splicing variant of RPSA leading to 5' UTR sequence alteration that causes congenital asplenia and a variant of TNF that could predispose to tuberculosis.

Humans↗

PubMed2026

A novel peptide encoded by circTLL1 drives osimertinib resistance in lung cancer by modulating the NT5C2/Ras/PI3K axis.

BACKGROUND: Acquired resistance to osimertinib, a third-generation EGFR tyrosine kinase inhibitor, remains a major clinical challenge in the treatment of non-small cell lung cancer (NSCLC). Although circular RNAs (circRNAs) have been increasingly implicated in drug resistance, most studies have focused on their canonical role as microRNA sponges, while their capacity to encode functional micropeptides remains largely unexplored. This study aimed to identify novel circRNAs involved in osimertinib resistance and to characterize their regulatory functions at the protein level. METHODS: Osimertinib-resistant (OR) NSCLC cell lines were established and validated. High-throughput RNA sequencing was performed to compare the circRNA expression profiles between parental and OR cells. The function of the candidate circRNA was assessed through a series of in vitro and in vivo experiments, including cell viability assays, apoptosis analysis, and xenograft mouse models. Mechanistic investigations involved mass spectrometry, co-immunoprecipitation and western blotting to explore its protein-coding potential and downstream signaling pathways. RESULTS: We identified a novel circRNA, termed circTLL1, that was stably and significantly upregulated in OR-NSCLC cells. Functionally, overexpression of circTLL1 promoted osimertinib resistance, whereas its knockdown restored drug sensitivity both in vitro and in vivo. Mechanistically, we discovered that circTLL1 harbors an open reading frame (ORF) that is translated into a novel 90-amino-acid protein, which we designated circTLL1-90aa. Further investigation revealed that circTLL1-90aa directly interacts with and promotes the degradation of 5'-nucleotidase, cytosolic II (NT5C2), thereby uncoupling nucleotide metabolism from its normal regulatory constraints. The consequent downregulation of NT5C2 leads to elevated GTP levels and leading to the sustained activation of the downstream Ras/PI3K/AKT signaling pathway. CONCLUSION: Our findings unveil a previously unrecognized circRNA/micropeptide/metabolism cascade underlying osimertinib resistance. The identification of the circTLL1-90aa/NT5C2/Ras/PI3K axis not only expands the functional repertoire of the non-coding genome but also provides new insights into the complexity of drug resistance. Given its selective upregulation in resistant cells, circTLL1-90aa holds promise both as a predictive biomarker for treatment stratification and as an actionable therapeutic target, offering a novel strategy to overcome osimertinib resistance in NSCLC patients.

Pyrimidines↗

PubMed1983

DNA sequences, gene regulation and modular protein evolution in the Drosophila 68C glue gene cluster.

The 68C locus of the Drosophila melanogaster polytene chromosomes contains the structural genes for three glue polypeptides (sgs-3, sgs-7 and sgs-8) synthesized in the larval salivary glands during the third larval instar. When the messenger RNAs for the glue polypeptides are being synthesized, the locus is puffed; the puff regresses in response to the steroid hormone ecdysterone. The three 68C glue mRNAs are coded in a gene cluster of less than 5000 base-pairs, and are expressed co-ordinately. In the experiments described here we show that the coordinate expression of these RNAs does not result from amplification of the puff DNA, nor is it associated with puff DNA rearrangement. We also report the nucleotide sequence of 6751 base-pairs of genomic DNA that includes the entire gene cluster, and describe coding and non-coding sequences with possible regulatory roles. In addition, we deduce the amino acid sequences of the primary translation products of the glue mRNAs, and show that the glue proteins form a diverged gene family. The members of the family all contain an amino-terminal hydrophobic block of amino acids, which is absent in the mature, secreted glue proteins, and a cysteine-rich carboxy-terminal module. sgs-3 differs from sgs-7 and sgs-8 by containing a third module between the other two, comprised largely of tandem repeats of the five amino acids Pro-Thr-Thr-Thr-Lys.

Amino Acid Sequence↗

PubMed1983

Yeast H3 and H4 histone messenger RNAs are transcribed from two non-allelic gene sets.

The genes coding for the H3 and H4 histones of Saccharomyces cerevisiae have been isolated by recombinant DNA cloning. The genes were detected in a bacteriophage lambda library of the yeast genome by hybridization with plasmids containing the cloned Psammechinus miliaris sea urchin histone genes (pCH7) and the cloned Drosophila histone genes (cDM500). Two non-allelic sets of the H3 and H4 genes have been isolated. Each set consists of one H3 gene and one H4 gene arranged as a divergently transcribed pair separated by an intergene spacer DNA. The histone genes were located on the cloned yeast fragments by S1 nuclease mapping, as was a gene (SMT1) of unknown function that does not code for a histone but is closely linked to one of the histone sets. Sequence homology between the two non-allelic sets is confined to the coding regions of the respective genes while the flanking DNA and intergene spacer DNA are extensively divergent. Cellular RNA homologous to the histone genes, including transcribed non-coding sequences unique to each of the four genes, was detected by S1 mapping, thus demonstrating that all four genes are transcribed in vegetative cells.

Base Sequence↗

PubMed1984

Binding of Xenopus transcription factor A to 5S RNA and to single stranded DNA.

Footprint competition assays are utilized to study the binding of Xenopus transcription factor A to a variety of single-stranded nucleic acids. The addition of Xenopus oocyte, yeast, or wheat germ 5S RNA as footprint competitors reveals that factor A binds these 5S RNAs with similar affinity. In contrast, factor A does not bind to E.coli 5S RNA or wheat germ tRNA in this assay. Factor A binding to single stranded DNA is also examined using footprint competition. Factor A binds preferentially to non-specific single stranded (M13) DNA versus double stranded (pBR322) DNA. Factor A binds equally well to single stranded DNA fragments containing either the coding or non-coding strands of the 5S RNA gene. Using single stranded M13 DNA as a competitor, the factor A-5S RNA gene complex is found to dissociate with a half-life of 5-6 min.

Animals↗

PubMed1985

Common structural features of the genes for two stable RNAs from Halobacterium halobium.

The genes coding for the 5S rRNA and another stable RNA, termed 7S RNA, in Halobacterium halobium were isolated from a genomic library of this archaebacterium and their nucleotide sequences determined. Both genes are colinear with their transcripts (5S rRNA and 7S RNA), but 5S rRNA and possibly also 7S RNA isolated from other halobacteria carry additional nucleotides within the RNA transcript. Both genes are located in the G + C rich chromosomal fraction I of H. halobium. Comparison of the 3' non-coding regions of both genes shows a 20 bp sequence of high homology immediately at the 3' ends which is almost symmetrically flanked by two stem-loop structures, one being situated close to the 3' end but within the coding region and the other downstream of the common 20 bp sequence.

Base Sequence↗

PubMed1986

Molecular determinants of alphavirus neurovirulence: nucleotide and deduced protein sequence changes during attenuation of Venezuelan equine encephalitis virus.

The nucleotide and deduced amino acid sequences of the structural proteins of the TC-83 vaccine strain of Venezuelan equine encephalitis (VEE) virus have been determined from a cDNA clone containing the 26S mRNA coding region. A cDNA clone encoding the equivalent region of the virulent parent VEE virus [Trinidad donkey strain (TRD)] has been sequenced previously. Comparison of the sequences of the TC-83 and TRD cDNA clones revealed 13 nucleotide differences. Neither the organization of the structural proteins (5'-capsid-E3-E2-6K-E1-3') nor the length (3762 nucleotides) of the open reading frame coding for the viral polyprotein precursor was altered during attenuation. Of the 13 nucleotide differences between the cDNA clones of TC-83 and TRD, nine occurred in the dominant population of the respective genomic RNAs from plaque-purified viruses. Six of the nine mutations were clustered in the E2 surface glycoprotein gene. All five of the nucleotide changes which produced non-conservative amino acid substitutions in the encoded proteins were located in the E2 gene. Two mutations occurred in the E1 glycoprotein gene; one was silent and the other did not alter the chemical character of the E1 protein. One nucleotide difference was found in the non-coding region immediately preceding the 5'-end of the 26S mRNA. The E2 and non-coding region mutations are candidates for the molecular determinants of VEE virus neurovirulence.

Amino Acid Sequence↗