Normal and pathogenic variation of RFC1 repeat expansions: implications for clinical diagnosis

Brain, Год журнала: 2023, Номер 146(12), С. 5060 - 5069

Опубликована: Июль 14, 2023

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing data from nearly 10 000 individuals recruited within the Genomics England project to investigate normal pathogenic variation of RFC1 repeat. We identified three novel motifs, AGGGC (n = 6 five families), AAGGC 2 one family) AGAGG 1), associated with CANVAS homozygous or compound heterozygous state common expansion. While AAAAG, AAAGGG AAGAG appear be benign, revealed a role for large AAAGG configuration 5). Long-read was used characterize entire sequence, six patients exhibited pure expansion, while other presented complex motifs interruptions. All appeared have arisen haplotype were predicted form highly stable G quadruplexes, which previously been demonstrated affect gene transcription conditions. The assessment these configurations warranted negative inconclusive genetic testing. Particular attention should paid carriers AAGGG/AAAGG when motif very (>500 repeats) interrupted. Accurate sizing full satellite long-read recommended clinically selected cases enable accurate molecular diagnosis counsel their families.

Язык: Английский

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Expanding the horizons of targeted protein degradation: A non-small molecule perspective

Acta Pharmaceutica Sinica B, Год журнала: 2024, Номер 14(6), С. 2402 - 2427

Опубликована: Янв. 21, 2024

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel

Язык: Английский

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G-quadruplex DNA: A Longer Story

Accounts of Chemical Research, Год журнала: 2022, Номер 55(22), С. 3242 - 3252

Опубликована: Окт. 25, 2022

ConspectusG-quadruplexes (G4s) are distinctive four-stranded DNA or RNA structures found within cells that thought to play functional roles in gene regulation and transcription, translation, recombination, damage/repair. While G4 can be uni-, bi-, tetramolecular with respect strands, folded unimolecular conformations most significant vivo. Unimolecular potentially form sequences runs of guanines interspersed what will become loops the structure: 5′GxLyGxLyGxLyGx, where x is typically 2–4 y highly variable. Such conserved specifically located genomes. In structure, from each run combine planar tetrads four hydrogen-bonded guanine bases; these stack on one another produce strand segments aligned specific parallel antiparallel orientations, connected by loop sequences. Three types (lateral, diagonal, "propeller") have been identified. The stacked a central cavity features strong coordination sites for monovalent cations stabilize potassium sodium preferred. A single monomeric forms sequence containing roughly 20–30 nucleotides. short primary focus X-ray crystallographic NMR studies produced high-resolution variety conformations. These often used as basis drug design efforts modulate function.We believe formed such perhaps myopic. structural arbitrarily selected removed their native genomic context, then changed base substitutions deletions intended optimize formation homogeneous conformation. We instead G-quadruplexes prefer company longer natural context multiple adjacent units into more complex multimeric richer topographies than simple forms. Bioinformatic searches human genome show potential forming common. Telomeric DNA, example, has single-stranded overhang hundreds nucleotides requisite repetitive G4s. Numerous extended promoter similar potentials formation. crystallography methods challenged (>30 nt), so other tools needed explore possible landscape. implemented an integrated biology approach address this challenge. This integrates experimental biophysical results atomic-level molecular modeling dynamics simulations provide quantitatively testable model structures. every long we studied far, readily form, surprising diversity dependent exact used. some cases, stable hairpin duplexes along even Account provides overview our recent progress new perspective G-quadruplex folding

Язык: Английский

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The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 13, 2023

Abstract Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion the intronic hexanucleotide repeat (GGGGCC) n in C9orf72 . Here, we investigate formation nucleic acid secondary structures these repeats, their role generating condensates characteristic We observe significant aggregation sequence , which associate to multimolecular G-quadruplexes (mG4s) by using range biophysical techniques. Exposing G4-unfolding conditions leads prompt disassembly, highlighting key mG4-formation condensation process. further validate biological relevance our findings detecting an increased prevalence G4-structures mutant human motor neurons when compared healthy staining with G4-selective fluorescent probe, revealing signal putative condensates. Our strongly suggest RNA G-rich repetitive sequences can form protein-free sustained G-quadruplexes, potential as therapeutic targets for mutation-related

Язык: Английский

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G-quadruplex folding in Xist RNA antagonizes PRC2 activity for stepwise regulation of X chromosome inactivation

Molecular Cell, Год журнала: 2024, Номер 84(10), С. 1870 - 1885.e9

Опубликована: Май 1, 2024

Язык: Английский

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Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine

American Journal of Respiratory and Critical Care Medicine, Год журнала: 2024, Номер 210(4), С. 401 - 423

Опубликована: Апрель 4, 2024

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) other progressive fibrotic interstitial lung diseases (ILDs), emphasizing contribution heritable factors. This state-of-the-art review synthesizes evidence on significant contributors to (PF), including rare variants common single nucleotide polymorphisms (SNPs). The MUC5B promoter variant is unusual, a SNP that markedly elevates risk early established PF. We address utility variation in enhancing understanding disease pathogenesis, clinical phenotypes, improving definitions, informing prognosis treatment response. Critical research gaps are highlighted, particularly underrepresentation non-European ancestries PF studies exploration phenotypes beyond usual pneumonia (UIP)/IPF. discuss role telomere length, often critically short PF, its link progression mortality, underscoring complexity involving biology genes (TERT, TERC) others like SFTPC MUC5B. Additionally, we potential gene-by-environment interactions modulate manifestation, advocating for precision medicine Insights from gene expression profiling multi-omic analyses highlight promise pathogenesis offer new approaches care, therapeutic drug development, biomarker discovery. Finally, ethical, legal, social implications therapies stressing need sound practices informed discussions. Looking forward, advocate comprehensive testing panels polygenic scores improve management related ILDs across diverse populations.

Язык: Английский

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Long-range DNA interactions: inter-molecular G-quadruplexes and their potential biological relevance

Chemical Communications, Год журнала: 2022, Номер 58(92), С. 12753 - 12762

Опубликована: Янв. 1, 2022

Guanine-rich DNA sequences are known to fold into secondary structures called G-quadruplexes (G4s), which can form from either individual strands (intra-molecular) or multiple (inter-molecular, iG4s). Intra-molecular G4s have been the object of extensive biological investigation due their enrichment in gene-promoters and telomers. On other hand, iG4s never considered contexts, as interaction between distal an iG4 cells was always deemed highly unlikely. In this feature article, we challenge dogma by presenting our recent discovery first human protein (CSB) displaying astonishing picomolar affinity binding selectivity for iG4s. These findings suggest potential highlight need further studies unravel fundamental roles these inter-molecular structures. Furthermore, discuss how formation neuronal cells, triggered repeat expansions C9orf72 gene, lead nucleic-acids based pathological aggregates neurodegenerative diseases like ALS FTD. Finally, on work short LNA-modified probes, provide a prespective rational design G4-selective chemical tools be leveraged elucidate relevance context ageing-related diseases.

Язык: Английский

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Structural Motifs at the Telomeres and Their Role in Regulatory Pathways

Biochemistry, Год журнала: 2024, Номер 63(7), С. 827 - 842

Опубликована: Март 14, 2024

Telomeres are specialized structures, found at the ends of linear chromosomes in eukaryotic cells, that play a crucial role maintaining stability and integrity genomes. They composed repetitive DNA sequences, ssDNA overhangs, several associated proteins. The length telomeres is linked to cellular aging humans, deficiencies their maintenance with various diseases. Key structural motifs serve protect vulnerable chromosomal ends. Telomeric also has ability form diverse complex higher-order including T-loops, D-loops, R-loops, G-loops, G-quadruplexes, i-motifs, complementary C-rich strand. While many essential proteins have been identified, intricacies interactions details still not fully understood. This Perspective highlights recent advancements comprehending structures human telomeres. It emphasizes significance telomeres, explores telomeric motifs, delves into biology surrounding telomerase. Furthermore, loops, topologies, contribute safeguarding discussed.

Язык: Английский

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Structural Unfolding of G-Quadruplexes: From Small Molecules to Antisense Strategies

Molecules, Год журнала: 2024, Номер 29(15), С. 3488 - 3488

Опубликована: Июль 25, 2024

G-quadruplexes (G4s) are non-canonical nucleic acid secondary structures that have gathered significant interest in medicinal chemistry over the past two decades due to their unique structural features and potential roles a variety of biological processes disorders. Traditionally, research efforts focused on stabilizing G4s, while recent years, attention has progressively shifted G4 destabilization, unveiling new therapeutic perspectives. This review provides an in-depth overview advances development small molecules, starting with controversial role TMPyP4. Moreover, we described effective metal complexes addition G4-disrupting molecules as well good ligands can destabilize G4s response external stimuli. Finally, presented antisense strategies promising approach for destabilizing particular focus 2'-OMe oligonucleotide, peptide acid, locked acid. Overall, this emphasizes importance understanding dynamics ongoing develop selective G4-unfolding modulate function potential.

Язык: Английский

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Thiophene-Extended Fluorescent Nucleosides as Molecular Rotor-Type Fluorogenic Sensors for Biomolecular Interactions

ACS Sensors, Год журнала: 2023, Номер 8(2), С. 923 - 932

Опубликована: Фев. 6, 2023

Fluorescent molecular rotors are versatile tools for the investigation of biomolecular interactions and monitoring microenvironmental changes in biological systems. They can transform invisible information into a fluorescence signal as straightforward response. Their utility is synergistically amplified when they merged with biomolecules. Despite tremendous significance superior programmability nucleic acids, there very few reports on development rotor-type isomorphic nucleosides. Here, we report synthesis characterization highly emissive rotor-containing thymine nucleoside (ThexT) its 2′-O-methyluridine analogue (2′-OMe-ThexU) fluorogenic microenvironment-sensitive sensors that emit vivid via an interaction target proteins. ThexT 2′-OMe-ThexU may potentially serve robust probes broad range applications, such mapping, to monitor viscosity specific protein-binding

Язык: Английский

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