RNA最新文献 - Book学术

Beyond RNA-binding domains: determinants of protein-RNA binding. 超越 RNA 结合域：蛋白质与 RNA 结合的决定因素。

IF 4.2 3区生物学

RNA Pub Date : 2024-11-18 DOI: 10.1261/rna.080026.124

Inbal Zigdon, Miri Carmi, Sagie Brodsky, Zohar Rosenwaser, Naama Barkai, Felix Jonas

引用次数: 0

RNA: Reviewers for Volume 30, 2024. RNA：第 30 卷（2024 年）审稿人。

IF 4.2 3区生物学

RNA Pub Date : 2024-11-18

引用次数: 0

Identification, characterization, and structure of a tRNA splicing enzyme RNA 5'-OH kinase from the pathogenic fungi Mucorales. 病原真菌 Mucorales 的 tRNA 剪接酶 RNA 5'-OH 激酶的鉴定、表征和结构。

IF 4.2 3区生物学

RNA Pub Date : 2024-11-18 DOI: 10.1261/rna.080247.124

Shreya Ghosh, Gina Wimberly-Gard, Agata Jacewicz, Beate Schwer, Stewart Shuman

{"title":"Identification, characterization, and structure of a tRNA splicing enzyme RNA 5'-OH kinase from the pathogenic fungi Mucorales.","authors":"Shreya Ghosh, Gina Wimberly-Gard, Agata Jacewicz, Beate Schwer, Stewart Shuman","doi":"10.1261/rna.080247.124","DOIUrl":"10.1261/rna.080247.124","url":null,"abstract":"Fungal Trl1 is an essential tRNA splicing enzyme composed of C-terminal cyclic phosphodiesterase and central polynucleotide kinase end-healing domains that convert the 2',3'-cyclic-PO4 and 5'-OH ends of tRNA exons into the 3'-OH,2'-PO4 and 5'-PO4 termini required for sealing by an N-terminal ATP-dependent ligase domain. Trifunctional Trl1 enzymes are present in most human fungal pathogens and are untapped targets for antifungal drug discovery. Mucorales species, deemed high-priority human pathogens by WHO, elaborate a noncanonical tRNA splicing apparatus in which a stand-alone monofunctional RNA ligase enzyme joins 3'-OH,2'-PO4 and 5'-PO4 termini. Here we identify a stand-alone Mucor circinelloides polynucleotide kinase (MciKIN) and affirm its biological activity in tRNA splicing by genetic complementation in yeast. Recombinant MciKIN catalyzes magnesium-dependent phosphorylation of 5'-OH RNA and DNA ends in vitro. MciKIN displays a strong preference for GTP as the phosphate donor in the kinase reaction, a trait shared with the stand-alone RNA kinase homologs from Mucorales species Rhizopus azygosporus (RazKIN) and Lichtheimia corymbifera (LcoKIN) and with the kinase domains of fungal Trl1 enzymes. We report a 1.65 Å crystal structure of RazKIN in complex with GDP•Mg2+ that illuminates the basis for guanosine nucleotide specificity.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"1674-1685"},"PeriodicalIF":4.2,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Escherichia coli ribB riboswitch senses flavin mononucleotide within a defined transcriptional window. 大肠杆菌 ribB 核糖开关能在确定的转录窗口内感知黄素单核苷酸。

IF 4.2 3区生物学

RNA Pub Date : 2024-11-18 DOI: 10.1261/rna.080074.124

Sébastien H Eschbach, Elsa D M Hien, Tithi Ghosh, Anne-Marie Lamontagne, Daniel A Lafontaine

{"title":"The Escherichia coli ribB riboswitch senses flavin mononucleotide within a defined transcriptional window.","authors":"Sébastien H Eschbach, Elsa D M Hien, Tithi Ghosh, Anne-Marie Lamontagne, Daniel A Lafontaine","doi":"10.1261/rna.080074.124","DOIUrl":"10.1261/rna.080074.124","url":null,"abstract":"Riboswitches are metabolite-binding RNA regulators that modulate gene expression at the levels of transcription and translation. One of the hallmarks of riboswitch regulation is that they undergo structural changes upon metabolite binding. While a lot of effort has been put to characterize how the metabolite is recognized by the riboswitch, there is still relatively little information regarding how ligand sensing is performed within a transcriptional context. Here, we study the ligand-dependent cotranscriptional folding of the FMN-sensing ribB riboswitch of Escherichia coli Using RNase H assays to study nascent ribB riboswitch transcripts, DNA probes targeting the P1 and sequestering stems indicate that FMN binding leads to the protection of these regions from RNase H cleavage, consistent with the riboswitch inhibiting translation initiation when bound to FMN. Our results show that ligand sensing is strongly affected by the position of elongating RNA polymerase, which is defining an FMN-binding transcriptional window that is bordered in its 3' extremity by a transcriptional pause site. Also, using successively overlapping DNA probes targeting a subdomain of the riboswitch, our data suggest the presence of a previously unsuspected helical region involving the 3' strand of the P1 stem. Our results show that this helical region is conserved across bacterial species, thus suggesting that this predicted structure, the anti*-P1 stem, is involved in the FMN-free conformation of the ribB riboswitch. Overall, our study further demonstrates that intricate folding strategies may be used by riboswitches to perform metabolite sensing during the transcriptional process.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"1660-1673"},"PeriodicalIF":4.2,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571811/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Independent neofunctionalization of Dxo1 in Saccharomyces and Candida led to 25S rRNA processing function. 酵母菌和念珠菌中 Dxo1 的独立新功能化导致了 25S rRNA 处理功能。

IF 4.2 3区生物学

RNA Pub Date : 2024-11-18 DOI: 10.1261/rna.080210.124

Jennifer E Hurtig, Catherine J Stuart, Ambro van Hoof

引用次数: 0

Site-blocking antisense oligonucleotides as a mechanism to fine-tune MeCP2 expression. 作为微调 MECP2 表达机制的定点阻断反义寡核苷酸

IF 4.2 3区生物学

RNA Pub Date : 2024-11-18 DOI: 10.1261/rna.080220.124

Amanda M Vanderplow, Grace E Dodis, Yewon Rhee, Jakub J Cikowski, Sonia Gonzalez, Mackenzie L Smith, Rocco G Gogliotti

{"title":"Site-blocking antisense oligonucleotides as a mechanism to fine-tune MeCP2 expression.","authors":"Amanda M Vanderplow, Grace E Dodis, Yewon Rhee, Jakub J Cikowski, Sonia Gonzalez, Mackenzie L Smith, Rocco G Gogliotti","doi":"10.1261/rna.080220.124","DOIUrl":"10.1261/rna.080220.124","url":null,"abstract":"Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Despite its severe phenotypes, studies in mouse models suggest that restoring MeCP2 levels can reverse RTT symptomology. Nevertheless, traditional gene therapy approaches are hindered by MeCP2's narrow therapeutic window, complicating the safe delivery of viral constructs without overshooting the threshold for toxicity. The 3' untranslated region (3' UTR) plays a key role in gene regulation, where factors like miRNAs bind to pre-mRNA and fine-tune expression. Given that each miRNA's contribution is modest, blocking miRNA binding may represent a potential therapeutic strategy for diseases with high dosage sensitivity, like RTT. Here, we present a series of site-blocking antisense oligonucleotides (sbASOs) designed to outcompete repressive miRNA binding at the MECP2 3' UTR. This strategy aims to increase MeCP2 levels in patients with missense or late-truncating mutations, where the hypomorphic nature of the protein can be offset by enhanced abundance. Our results demonstrate that sbASOs can elevate MeCP2 levels in a dose-dependent manner in SH-SY5Y and patient fibroblast cell lines, plateauing at levels projected to be safe. Confirming in vivo functionality, sbASO administration in wild-type mice led to significant Mecp2 upregulation and the emergence of phenotypes associated with Mecp2 overexpression. In a T158M neural stem cell model of RTT, sbASO treatment significantly increased MeCP2 expression and levels of the downstream effector protein brain-derived neurotrophic factor (BDNF). These findings highlight the potential of sbASO-based therapies for MeCP2-related disorders and advocate for their continued development.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"1554-1571"},"PeriodicalIF":4.2,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploring the energetic and conformational properties of the sequence space connecting naturally occurring RNA tetraloop receptor motifs. 探索连接天然存在的 RNA 四环受体图案的序列空间的能量和构象特性。

IF 4.2 3区生物学

RNA Pub Date : 2024-11-18 DOI: 10.1261/rna.080039.124

John H Shin, Lena M Cuevas, Rohit Roy, Steve L Bonilla, Hashim Al-Hashimi, William J Greenleaf, Daniel Herschlag

{"title":"Exploring the energetic and conformational properties of the sequence space connecting naturally occurring RNA tetraloop receptor motifs.","authors":"John H Shin, Lena M Cuevas, Rohit Roy, Steve L Bonilla, Hashim Al-Hashimi, William J Greenleaf, Daniel Herschlag","doi":"10.1261/rna.080039.124","DOIUrl":"10.1261/rna.080039.124","url":null,"abstract":"Folded RNAs contain tertiary contact motifs whose structures and energetics are conserved across different RNAs. The transferable properties of RNA motifs simplify the RNA folding problem, but measuring energetic and conformational properties of many motifs remains a challenge. Here, we use a high-throughput thermodynamic approach to investigate how sequence changes alter the binding properties of naturally occurring motifs, the GAAA tetraloop • tetraloop receptor (TLR) interactions. We measured the binding energies and conformational preferences of TLR sequences that span mutational pathways from the canonical 11ntR to two other natural TLRs, the IC3R and Vc2R. While the IC3R and Vc2R share highly similar energetic and conformational properties, the landscapes that map the sequence changes for their conversion from the 11ntR to changes in these properties differ dramatically. Differences in the energetic landscapes stem from the mutations needed to convert the 11ntR to the IC3R and Vc2R rather than a difference in the intrinsic energetic architectures of these TLRs. The conformational landscapes feature several nonnative TLR variants with conformational preferences that differ from both the initial and final TLRs; these species represent potential branching points along the multidimensional sequence space to sequences with greater fitness in other RNA contexts with alternative conformational preferences. Our high-throughput, quantitative approach reveals the complex nature of sequence-fitness landscapes and leads to models for their molecular origins. Systematic and quantitative molecular approaches provide critical insights into understanding the evolution of natural RNAs as they traverse complex landscapes in response to selective pressures.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"1646-1659"},"PeriodicalIF":4.2,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571812/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sod1-deficient cells are impaired in formation of the modified nucleosides mcm⁵s²U and yW in tRNA. Sod1 缺陷细胞在 tRNA 中形成修饰核苷 mcm5s2U 和 yW 的能力受损。

IF 4.2 3区生物学

RNA Pub Date : 2024-11-18 DOI: 10.1261/rna.080181.124

Fu Xu, Anders S Byström, Marcus J O Johansson

{"title":"Sod1-deficient cells are impaired in formation of the modified nucleosides mcm5s2U and yW in tRNA.","authors":"Fu Xu, Anders S Byström, Marcus J O Johansson","doi":"10.1261/rna.080181.124","DOIUrl":"10.1261/rna.080181.124","url":null,"abstract":"Uridine residues present at the wobble position of eukaryotic cytosolic tRNAs often carry a 5-carbamoylmethyl (ncm5), 5-methoxycarbonylmethyl (mcm5), or 5-methoxycarbonylhydroxymethyl (mchm5) side-chain. The presence of these side-chains allows proper pairing with cognate codons, and they are particularly important in tRNA species where the U34 residue is also modified with a 2-thio (s2) group. The first step in the synthesis of the ncm5, mcm5, and mchm5 side-chains is dependent on the six-subunit Elongator complex, whereas the thiolation of the 2-position is catalyzed by the Ncs6/Ncs2 complex. In both yeast and metazoans, allelic variants of Elongator subunit genes show genetic interactions with mutant alleles of SOD1, which encodes the cytosolic Cu, Zn-superoxide dismutase. However, the cause of these genetic interactions remains unclear. Here, we show that yeast sod1 null mutants are impaired in the formation of 2-thio-modified U34 residues. In addition, the lack of Sod1 induces a defect in the biosynthesis of wybutosine, which is a modified nucleoside found at position 37 of tRNAPhe Our results suggest that these tRNA modification defects are caused by superoxide-induced inhibition of the iron-sulfur cluster-containing Ncs6/Ncs2 and Tyw1 enzymes. Since mutations in Elongator subunit genes generate strong negative genetic interactions with mutant ncs6 and ncs2 alleles, our findings at least partially explain why the activity of Elongator can modulate the phenotypic consequences of SOD1/sod1 alleles. Collectively, our results imply that tRNA hypomodification may contribute to impaired proteostasis in Sod1-deficient cells.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":"1586-1595"},"PeriodicalIF":4.2,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11571800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Two dynamic, N-terminal regions are required for function in Ribosomal RNA Adenine Dimethylase family members. 核糖体 RNA 腺嘌呤二甲基化酶家族成员的功能需要两个动态的 N 端区域。

IF 4.2 3区生物学

RNA Pub Date : 2024-11-08 DOI: 10.1261/rna.080068.124

Danielle A McGaha, Alexandrea Collins, Luqman O Ajisafe, Calvin C Perdigao, Jordan L Bondrowski, Karen Fetsch, Jack A Dunkle

{"title":"Two dynamic, N-terminal regions are required for function in Ribosomal RNA Adenine Dimethylase family members.","authors":"Danielle A McGaha, Alexandrea Collins, Luqman O Ajisafe, Calvin C Perdigao, Jordan L Bondrowski, Karen Fetsch, Jack A Dunkle","doi":"10.1261/rna.080068.124","DOIUrl":"10.1261/rna.080068.124","url":null,"abstract":"Prominent members of the Ribosomal RNA Adenine Dimethylase (RRAD) family of enzymes facilitate ribosome maturation by dimethylating two nucleotides of small subunit rRNA including the human DIMT1 and bacterial KsgA enzymes. A sub-group of RRAD enzymes, named erythromycin resistance methyltransferases (Erm) dimethylate a specific nucleotide in large subunit rRNA to confer antibiotic resistance. How these enzymes regulate methylation so that it only occurs on the specific substrate is not fully understood. While performing random mutagenesis on the catalytic domain of ErmE, we discovered that mutants in an N-terminal region of the protein that is disordered in the ErmE crystal structure are associated with a loss of antibiotic resistance. By subjecting site-directed mutants of ErmE and KsgA to phenotypic and in vitro assays we found that the N-terminal region is critical for activity in RRAD enzymes: the N-terminal basic region promotes rRNA binding and the conserved motif likely assists in juxtaposing the adenosine substrate and the SAM cofactor. Our results and emerging structural data suggest this dynamic, N-terminal region of RRAD enzymes becomes ordered upon rRNA binding forming a cap on the active site required for methylation.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142627183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of bioconjugate-based delivery systems for nucleic acids. 开发基于生物共轭物的核酸输送系统。

IF 4.2 3区生物学

RNA Pub Date : 2024-10-30 DOI: 10.1261/rna.080273.124

Aniket Wahane, Vishal Kasina, Mounika Pathuri, Ciara Marro-Wilson, Anisha Gupta, Frank J Slack, Raman Bahal

{"title":"Development of bioconjugate-based delivery systems for nucleic acids.","authors":"Aniket Wahane, Vishal Kasina, Mounika Pathuri, Ciara Marro-Wilson, Anisha Gupta, Frank J Slack, Raman Bahal","doi":"10.1261/rna.080273.124","DOIUrl":"https://doi.org/10.1261/rna.080273.124","url":null,"abstract":"Nucleic acids are a class of drugs that can modulate gene and protein expression by various mechanisms, namely, RNAi, mRNA degradation by RNase H cleavage, splice modulation, and steric blocking of protein binding or mRNA translation, thus exhibiting immense potential to treat various genetic and rare diseases. Unlike protein-targeted therapeutics, the clinical use of nucleic acids relies on Watson-Crick sequence recognition to regulate aberrant gene expression and impede protein translation. Though promising, targeted delivery remains a bottleneck for the clinical adoption of nucleic acid-based therapeutics. To overcome the delivery challenges associated with nucleic acids, various chemical modifications and bioconjugation-based delivery strategies have been explored. Currently, liver targeting by N-acetyl galactosamine (GalNAc) conjugation has been at the forefront for the treatment of rare and various metabolic diseases, which has led to FDA approval of four nucleic acid drugs. In addition, various other bioconjugation strategies have been explored to facilitate active organ and cell-enriched targeting. This review briefly covers the different classes of nucleic acids, their mechanisms of action, and their challenges. We also elaborate on recent advances in bioconjugation strategies in developing a diverse set of ligands for targeted delivery of nucleic acid drugs.","PeriodicalId":21401,"journal":{"name":"RNA","volume":" ","pages":""},"PeriodicalIF":4.2,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0