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Cell Reports Jul 2023Neurexin synaptic organizing proteins are central to a genetic risk pathway in neuropsychiatric disorders. Neurexins also exemplify molecular diversity in the brain,...
Neurexin synaptic organizing proteins are central to a genetic risk pathway in neuropsychiatric disorders. Neurexins also exemplify molecular diversity in the brain, with over a thousand alternatively spliced forms and further structural heterogeneity contributed by heparan sulfate glycan modification. Yet, interactions between these modes of post-transcriptional and post-translational modification have not been studied. We reveal that these regulatory modes converge on neurexin-1 splice site 5 (S5): the S5 insert increases the number of heparan sulfate chains. This is associated with reduced neurexin-1 protein level and reduced glutamatergic neurotransmitter release. Exclusion of neurexin-1 S5 in mice boosts neurotransmission without altering the AMPA/NMDA ratio and shifts communication and repetitive behavior away from phenotypes associated with autism spectrum disorders. Thus, neurexin-1 S5 acts as a synaptic rheostat to impact behavior through the intersection of RNA processing and glycobiology. These findings position NRXN1 S5 as a potential therapeutic target to restore function in neuropsychiatric disorders.
Topics: Animals; Mice; Alternative Splicing; Autistic Disorder; Brain; Heparitin Sulfate; Neural Cell Adhesion Molecules; Synapses; Synaptic Transmission
PubMed: 37384525
DOI: 10.1016/j.celrep.2023.112714 -
Clinical and Translational Medicine Oct 2023Background N6-methyladenosine (m6A), the most prevalent internal mRNA modification in eukaryotes, is added by m6A methyltransferases, removed by m6A demethylases and... (Review)
Review
Background N6-methyladenosine (m6A), the most prevalent internal mRNA modification in eukaryotes, is added by m6A methyltransferases, removed by m6A demethylases and recognised by m6A-binding proteins. This modification significantly influences carious facets of RNA metabolism and plays a pivotal role in cellular and physiological processes. Main body Pre-mRNA alternative splicing, a process that generates multiple splice isoforms from multi-exon genes, contributes significantly to the protein diversity in mammals. Moreover, the presence of crosstalk between m6A modification and alternative splicing, with m6A modifications on pre-mRNAs exerting regulatory control, has been established. The m6A modification modulates alternative splicing patterns by recruiting specific RNA-binding proteins (RBPs) that regulate alternative splicing or by directly influencing the interaction between RBPs and their target RNAs. Conversely, alternative splicing can impact the deposition or recognition of m6A modification on mRNAs. The integration of m6A modifications has expanded the scope of therapeutic strategies for cancer treatment, while alternative splicing offers novel insights into the mechanistic role of m6A methylation in cancer initiation and progression. Conclusion This review aims to highlight the biological functions of alternative splicing of m6A modification machinery and its implications in tumourigenesis. Furthermore, we discuss the clinical relevance of understanding m6A-dependent alternative splicing in tumour therapies.
Topics: Animals; Alternative Splicing; Neoplasms; RNA; Methylation; RNA, Messenger; RNA-Binding Proteins; Mammals
PubMed: 37850412
DOI: 10.1002/ctm2.1460 -
Journal of Structural Biology Sep 2023Alternative splicing of repeats in proteins provides a mechanism for rewiring and fine-tuning protein interaction networks. In this work, we developed a robust and...
Alternative splicing of repeats in proteins provides a mechanism for rewiring and fine-tuning protein interaction networks. In this work, we developed a robust and versatile method, ASPRING, to identify alternatively spliced protein repeats from gene annotations. ASPRING leverages evolutionary meaningful alternative splicing-aware hierarchical graphs to provide maps between protein repeats sequences and 3D structures. We re-think the definition of repeats by explicitly accounting for transcript diversity across several genes/species. Using a stringent sequence-based similarity criterion, we detected over 5,000 evolutionary conserved repeats by screening virtually all human protein-coding genes and their orthologs across a dozen species. Through a joint analysis of their sequences and structures, we extracted specificity-determining sequence signatures and assessed their implication in experimentally resolved and modelled protein interactions. Our findings demonstrate the widespread alternative usage of protein repeats in modulating protein interactions and open avenues for targeting repeat-mediated interactions.
Topics: Humans; Alternative Splicing; Proteins
PubMed: 37453591
DOI: 10.1016/j.jsb.2023.107997 -
Wiley Interdisciplinary Reviews. RNA 2024Disruptions in spatiotemporal gene expression can result in atypical brain function. Specifically, autism spectrum disorder (ASD) is characterized by abnormalities in... (Review)
Review
Disruptions in spatiotemporal gene expression can result in atypical brain function. Specifically, autism spectrum disorder (ASD) is characterized by abnormalities in pre-mRNA splicing. Abnormal splicing patterns have been identified in the brains of individuals with ASD, and mutations in splicing factors have been found to contribute to neurodevelopmental delays associated with ASD. Here we review studies that shed light on the importance of splicing observed in ASD and that explored the intricate relationship between splicing factors and ASD, revealing how disruptions in pre-mRNA splicing may underlie ASD pathogenesis. We provide an overview of the research regarding all splicing factors associated with ASD and place a special emphasis on five specific splicing factors-HNRNPH2, NOVA2, WBP4, SRRM2, and RBFOX1-known to impact the splicing of ASD-related genes. In the discussion of the molecular mechanisms influenced by these splicing factors, we lay the groundwork for a deeper understanding of ASD's complex etiology. Finally, we discuss the potential benefit of unraveling the connection between splicing and ASD for the development of more precise diagnostic tools and targeted therapeutic interventions. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution RNA Evolution and Genomics > Computational Analyses of RNA RNA-Based Catalysis > RNA Catalysis in Splicing and Translation.
Topics: Humans; Autism Spectrum Disorder; Autistic Disorder; RNA Precursors; RNA Splicing; RNA Splicing Factors; Neuro-Oncological Ventral Antigen
PubMed: 38509732
DOI: 10.1002/wrna.1838 -
Biochimica Et Biophysica Acta.... Oct 2023Alternative pre-mRNA splicing, which produces various mRNA isoforms with distinct structures and functions from a single gene, is regulated by specific RNA-binding... (Review)
Review
Alternative pre-mRNA splicing, which produces various mRNA isoforms with distinct structures and functions from a single gene, is regulated by specific RNA-binding proteins and is an essential method for regulating gene expression in mammals. Recent studies have shown that abnormal change during neuronal development triggered by splicing mis-regulation is an important feature of various neurological diseases. Polypyrimidine tract binding protein 1 (PTBP1) is a kind of RNA-binding proteins with extensive biological functions. As a well-known splicing regulator, it affects the neuronal development process through its involvement in axon formation, synaptogenesis, and neuronal apoptosis, according to the most recent studies. Here, we summarized the mechanism of alternative splicing, structure and function of PTBP1, and the latest research progress on the role of alternative splicing events regulated by PTBP1 in axon formation, synaptogenesis and neuronal apoptosis, to reveal the mechanism of PTBP1-regulated changes in neuronal development process.
Topics: Animals; Mammals; Polypyrimidine Tract-Binding Protein; RNA; RNA Splicing; RNA Splicing Factors; RNA-Binding Proteins; Nervous System Diseases; Neurogenesis
PubMed: 37263298
DOI: 10.1016/j.bbamcr.2023.119506 -
Cellular and Molecular Life Sciences :... Nov 2023To be functional, some RNAs require a processing step involving splicing events. Each splicing event necessitates an RNA ligation step. RNA ligation is a process that... (Review)
Review
To be functional, some RNAs require a processing step involving splicing events. Each splicing event necessitates an RNA ligation step. RNA ligation is a process that can be achieved with various intermediaries such as self-catalysing RNAs, 5'-3' and 3'-5' RNA ligases. While several types of RNA ligation mechanisms occur in human, RtcB is the only 3'-5' RNA ligase identified in human cells to date. RtcB RNA ligation activity is well known to be essential for the splicing of XBP1, an essential transcription factor of the unfolded protein response; as well as for the maturation of specific intron-containing tRNAs. As such, RtcB is a core factor in protein synthesis and homeostasis. Taking advantage of the high homology between RtcB orthologues in archaea, bacteria and eukaryotes, this review will provide an introduction to the structure of RtcB and the mechanism of 3'-5' RNA ligation. This analysis is followed by a description of the mechanisms regulating RtcB activity and localisation, its known partners and its various functions from bacteria to human with a specific focus on human cancer.
Topics: Humans; RNA Ligase (ATP); Transcription Factors; RNA; Unfolded Protein Response; RNA, Transfer; RNA Splicing
PubMed: 37935993
DOI: 10.1007/s00018-023-05001-5 -
Journal of Medicinal Chemistry Sep 2023Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin () gene. We report the design of a series of pre-mRNA splicing...
Huntington's disease (HD) is caused by an expanded CAG trinucleotide repeat in exon 1 of the huntingtin () gene. We report the design of a series of pre-mRNA splicing modulators that lower huntingtin (HTT) protein, including the toxic mutant huntingtin (mHTT), by promoting insertion of a pseudoexon containing a premature termination codon at the exon 49-50 junction. The resulting transcript undergoes nonsense-mediated decay, leading to a reduction of mRNA transcripts and protein levels. The starting benzamide core was modified to pyrazine amide and further optimized to give a potent, CNS-penetrant, and orally bioavailable -splicing modulator . This compound reduced canonical splicing of the RNA exon 49-50 and demonstrated significant HTT-lowering in both human HD stem cells and mouse BACHD models. Compound is a structurally diverse -splicing modulator that may help understand the mechanism of adverse effects such as peripheral neuropathy associated with branaplam.
PubMed: 37712656
DOI: 10.1021/acs.jmedchem.3c01173 -
Current Opinion in Structural Biology Aug 2023Proteins provide the basis for cellular function. Having multiple versions of the same protein within a single organism provides a way of regulating its activity or... (Review)
Review
Proteins provide the basis for cellular function. Having multiple versions of the same protein within a single organism provides a way of regulating its activity or developing novel functions. Post-translational modifications of proteins, by means of adding/removing chemical groups to amino acids, allow for a well-regulated and controlled way of generating functionally distinct protein species. Alternative splicing is another method with which organisms possibly generate new isoforms. Additionally, gene duplication events throughout evolution generate multiple paralogs of the same genes, resulting in multiple versions of the same protein within an organism. In this review, we discuss recent advancements in the study of these three methods of protein diversification and provide illustrative examples of how they affect protein structure and function.
Topics: Alternative Splicing; Gene Duplication; Evolution, Molecular; Protein Isoforms; Protein Processing, Post-Translational
PubMed: 37354790
DOI: 10.1016/j.sbi.2023.102640 -
Cells Dec 2023Alternative splicing changes are closely linked to aging, though it remains unclear if they are drivers or effects. As organisms age, splicing patterns change, varying... (Review)
Review
Alternative splicing changes are closely linked to aging, though it remains unclear if they are drivers or effects. As organisms age, splicing patterns change, varying gene isoform levels and functions. These changes may contribute to aging alterations rather than just reflect declining RNA quality control. Three main splicing types-intron retention, cassette exons, and cryptic exons-play key roles in age-related complexity. These events modify protein domains and increase nonsense-mediated decay, shifting protein isoform levels and functions. This may potentially drive aging or serve as a biomarker. Fluctuations in splicing factor expression also occur with aging. Somatic mutations in splicing genes can also promote aging and age-related disease. The interplay between splicing and aging has major implications for aging biology, though differentiating correlation and causation remains challenging. Declaring a splicing factor or event as a driver requires comprehensive evaluation of the associated molecular and physiological changes. A greater understanding of how RNA splicing machinery and downstream targets are impacted by aging is essential to conclusively establish the role of splicing in driving aging, representing a promising area with key implications for understanding aging, developing novel therapeutical options, and ultimately leading to an increase in the healthy human lifespan.
Topics: Humans; Alternative Splicing; RNA, Messenger; Protein Isoforms; RNA Splicing Factors; Aging; Nonsense Mediated mRNA Decay
PubMed: 38132139
DOI: 10.3390/cells12242819 -
Plant Physiology Aug 2023Pentatricopeptide repeat (PPR) proteins form a large protein family and have diverse functions in plant development. Here, we identified an ALBINO EMBRYO AND SEEDLING...
Pentatricopeptide repeat (PPR) proteins form a large protein family and have diverse functions in plant development. Here, we identified an ALBINO EMBRYO AND SEEDLING (AES) gene that encodes a P-type PPR protein expressed in various tissues, especially the young leaves of Arabidopsis (Arabidopsis thaliana). Its null mutant aes exhibited a collapsed chloroplast membrane system, reduced pigment content and photosynthetic activity, decreased transcript levels of PEP (plastid-encoded polymerase)-dependent chloroplast genes, and defective RNA splicing. Further work revealed that AES could directly bind to psbB-psbT, psbH-petB, rps8-rpl36, clpP, ycf3, and ndhA in vivo and in vitro and that the splicing efficiencies of these genes and the expression levels of ycf3, ndhA, and cis-tron psbB-psbT-psbH-petB-petD decreased dramatically, leading to defective PSI, PSII, and Cyt b6f in aes. Moreover, AES could be transported into the chloroplast stroma via the TOC-TIC channel with the assistance of Tic110 and cpSRP54 and may recruit HCF244, SOT1, and CAF1 to participate in the target RNA process. These findings suggested that AES is an essential protein for the assembly of photosynthetic complexes, providing insights into the splicing of psbB operon (psbB-psbT-psbH-petB-petD), ycf3, and ndhA, as well as maintaining chloroplast homeostasis.
Topics: Arabidopsis; Seedlings; Chloroplasts; RNA Splicing; Arabidopsis Proteins; Homeostasis; RNA, Chloroplast
PubMed: 37311175
DOI: 10.1093/plphys/kiad341