Pathogenic CANVAS (AAGGG)n repeats stall DNA replication due to the formation of alternative DNA structures DOI Creative Commons
Julia A. Hisey, Elina A. Radchenko,

Nicholas H Mandel

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 52(8), С. 4361 - 4374

Опубликована: Фев. 21, 2024

Abstract CANVAS is a recently characterized repeat expansion disease, most commonly caused by homozygous expansions of an intronic (A2G3)n in the RFC1 gene. There are multitude motifs found human population at this locus, some which pathogenic and others benign. In study, we conducted structure-functional analyses nonpathogenic (A4G)n repeats. We that pathogenic, but not nonpathogenic, presents potent, orientation-dependent impediment to DNA polymerization vitro. The pattern blockage consistent with triplex or quadruplex formation presence magnesium potassium ions, respectively. Chemical probing both repeats vitro reveals H-DNA only repeat. Consistently, bioinformatic analysis S1-END-seq data from cell lines shows preferential genome-wide over motifs. Finally, stalls replication fork progression yeast cells. hypothesize CANVAS-causing represents challenge genome stability folding into alternative structures stall replication.

Язык: Английский

Molecular mechanisms underlying nucleotide repeat expansion disorders DOI
Indranil Malik, Chase P. Kelley, Eric T. Wang

и другие.

Nature Reviews Molecular Cell Biology, Год журнала: 2021, Номер 22(9), С. 589 - 607

Опубликована: Июнь 17, 2021

Язык: Английский

Процитировано

258
DNA copy number variation: Main characteristics, evolutionary significance, and pathological aspects DOI Creative Commons
Ondrej Pös, Ján Radvánszky, Gergely Buglyó

и другие.

Biomedical Journal, Год журнала: 2021, Номер 44(5), С. 548 - 559

Опубликована: Фев. 15, 2021

Copy number variants (CNVs) were the subject of extensive research in past years. They are common features human genome that play an important role evolution, contribute to population diversity, development certain diseases, and influence host-microbiome interactions. CNVs have found application molecular diagnosis many diseases non-invasive prenatal care, but their full potential is only emerging. expected a tremendous impact on screening, diagnosis, prognosis, monitoring several disorders, including cancer cardiovascular disease. Here, we comprehensively review basic definitions term CNV, outline mechanisms factors involved CNV formation, discuss evolutionary pathological aspects. We suggest need for better defined distinguishing criteria boundaries between known types CNVs.

Язык: Английский

Процитировано

178
Repeat expansions confer WRN dependence in microsatellite-unstable cancers DOI
Niek van Wietmarschen, Sriram Sridharan, William J. Nathan

и другие.

Nature, Год журнала: 2020, Номер 586(7828), С. 292 - 298

Опубликована: Сен. 30, 2020

Язык: Английский

Процитировано

142
An update on the neurological short tandem repeat expansion disorders and the emergence of long-read sequencing diagnostics DOI Creative Commons
Sanjog R. Chintalaphani, Sandy S. Pineda, Ira W. Deveson

и другие.

Acta Neuropathologica Communications, Год журнала: 2021, Номер 9(1)

Опубликована: Май 25, 2021

Abstract Background Short tandem repeat (STR) expansion disorders are an important cause of human neurological disease. They have established role in more than 40 different phenotypes including the myotonic dystrophies, Fragile X syndrome, Huntington’s disease, hereditary cerebellar ataxias, amyotrophic lateral sclerosis and frontotemporal dementia. Main body STR expansions difficult to detect may explain unsolved diseases, as highlighted by recent findings including: discovery a biallelic intronic ‘AAGGG’ RFC1 ataxia, neuropathy, vestibular areflexia syndrome (CANVAS); finding ‘CGG’ NOTCH2NLC neuronal intranuclear inclusion disease range clinical phenotypes. However, laboratory techniques for diagnosis (repeat-primed PCR Southern blot) cumbersome, low-throughput poorly suited parallel analysis multiple gene regions. While next generation sequencing (NGS) has been increasingly used, short-read NGS platforms (e.g., Illumina) unable genotype large and/or complex expansions. Long-read recently developed Oxford Nanopore Technology Pacific Biosciences promise overcome these limitations deliver enhanced rapid cost-effective fashion. Conclusion We anticipate that long-read will rapidly transform detection short both discovery.

Язык: Английский

Процитировано

125
Multimeric G-quadruplexes: A review on their biological roles and targeting DOI Creative Commons
Ilaria Frasson, Valentina Pirota, Sara N. Richter

и другие.

International Journal of Biological Macromolecules, Год журнала: 2022, Номер 204, С. 89 - 102

Опубликована: Фев. 4, 2022

In human cells, nucleic acids adopt several non-canonical structures that regulate key cellular processes. Among them, G-quadruplexes (G4s) are stable form in guanine-rich regions vitro and cells. G4 folded/unfolded state shapes numerous processes, including genome replication, transcription, translation. Moreover, folding is involved genomic instability. G4s have been described to multimerize, forming high-order both DNA and/or RNA strands. Multimeric can be formed by adjacent intramolecular joined stacking interactions or connected short loops. also originate from the assembly of guanines embedded on independent Notably, crucial genome, such as 3'-terminal overhang telomeric well open reading frame genes preservation neuron viability central peripheral nervous system prone multimeric G4s. The biological importance has recently described, with playing potentially protective deleterious effects pathogenic cascade various diseases. Here, we portray multifaceted scenario G4s, terms structural properties, roles, targeting strategies.

Язык: Английский

Процитировано

74
Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications DOI
Indhu‐Shree Rajan‐Babu, Egor Dolzhenko, Michael A. Eberle

и другие.

Nature Reviews Genetics, Год журнала: 2024, Номер 25(7), С. 476 - 499

Опубликована: Март 11, 2024

Язык: Английский

Процитировано

26
Properties and biological impact of RNA G-quadruplexes: from order to turmoil and back DOI Creative Commons
Prakash Kharel,

Gertraud Becker,

Vladimir B. Tsvetkov

и другие.

Nucleic Acids Research, Год журнала: 2020, Номер 48(22), С. 12534 - 12555

Опубликована: Ноя. 7, 2020

Guanine-quadruplexes (G4s) are non-canonical four-stranded structures that can be formed in guanine (G) rich nucleic acid sequences. A great number of G-rich sequences capable forming G4 have been described based on vitro analysis, and evidence supporting their formation live cells continues to accumulate. While DNA G4s (dG4s) within chromatin vivo has supported by different chemical, imaging genomic approaches, RNA (rG4s) remains a matter discussion. Recent data support the dynamic nature transcriptome. Such fluctuation rG4 folding-unfolding underpins biological significance these regulation metabolism. Moreover, rG4-mediated functions may ultimately connected mechanisms underlying disease pathologies and, potentially, provide novel options for therapeutics. In this framework, we will review landscape rG4s transcriptome, focus potential impact processes, consider an emerging connection human health disease.

Язык: Английский

Процитировано

131
Non-B DNA: a major contributor to small- and large-scale variation in nucleotide substitution frequencies across the genome DOI Creative Commons
Wilfried M. Guiblet, Marzia A. Cremona, Robert S. Harris

и другие.

Nucleic Acids Research, Год журнала: 2021, Номер 49(3), С. 1497 - 1516

Опубликована: Янв. 13, 2021

Abstract Approximately 13% of the human genome can fold into non-canonical (non-B) DNA structures (e.g. G-quadruplexes, Z-DNA, etc.), which have been implicated in vital cellular processes. Non-B also hinders replication, increasing errors and facilitating mutagenesis, yet its contribution to genome-wide variation mutation rates remains unexplored. Here, we conducted a comprehensive analysis nucleotide substitution frequencies at non-B loci within noncoding, non-repetitive regions, their ±2 kb flanking 1-Megabase windows, using human-orangutan divergence single-nucleotide polymorphisms. Functional data single-base resolution demonstrated that are usually elevated DNA, with patterns specific each type. Mirror, direct inverted repeats higher spacers than repeat arms, whereas particularly stable ones, loops stems. Several types affect regions. Finally, explains more any other predictor multiple regression models for diversity or scale. Thus, substantially contributes small large scales. Our results highlight role germline mutagenesis implications evolution genetic diseases.

Язык: Английский

Процитировано

89
Activation of homologous recombination in G1 preserves centromeric integrity DOI
Duygu Yilmaz,

Audrey Furst,

Karen J. Meaburn

и другие.

Nature, Год журнала: 2021, Номер 600(7890), С. 748 - 753

Опубликована: Дек. 1, 2021

Язык: Английский

Процитировано

84
A hexanucleotide repeat modifies expressivity of X‐linked dystonia parkinsonism DOI
Ana Westenberger, Charles Jourdan Reyes, Gerard Saranza

и другие.

Annals of Neurology, Год журнала: 2019, Номер 85(6), С. 812 - 822

Опубликована: Апрель 12, 2019

X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, (CCCTCT)n repeat within the SVA has been reported as an age-at-onset (AAO) modifier XDP. Here we investigate role of this hexanucleotide modifying expressivity XDP.We genotyped 355 XDP patients and correlated number (RN) with AAO (n = 295), initial clinical manifestation 294), site onset 238), disease severity 28), cognitive function 15). Furthermore, investigated i) instability segregation analysis Southern blotting using postmortem brain samples from two affected individuals ii) relative TAF1 expression blood RNA 31 patients.RN showed significant inverse correlations positive correlation dysfunction. Importantly, (and not RN) was directly associated whether or will manifest at onset. RN lower mouth/tongue compared blepharospasm. unstable across germline transmissions overall tendency to increase length exhibited somatic mosaicism brain.The acts genetic RN-dependent repression subsequent differences mRNA levels may be potentiated through variability leading neurological phenotype. ANN NEUROL 2019;85:812-822.

Язык: Английский

Процитировано

81