More technically, Cas9 is a dual RNA-guided DNA endonuclease enzyme associated with the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) adaptive immune system in Streptococcus pyogenes. (wikipedia.org)
Instability17
Pathological mutations involving noncoding microsatellite repeats are typically located near promoters in CpG islands and are coupled with extensive repeat instability when sufficiently long. (huji.ac.il)
What causes these regions to be prone to repeat instability is not fully understood. (huji.ac.il)
There is a general consensus that instability results from the induction of unusual structures in the DNA by the repeats as a consequence of mispairing between complementary strands. (huji.ac.il)
In addition, there is some evidence that repeat instability is mediated by RNA transcription through the formation of three-stranded nucleic structures composed of persistent DNA:RNA hybrids, concomitant with single-strand DNA displacements (R-loops). (huji.ac.il)
These interruptions are likely to reflect unusual structures in the DNA that drive repeat instability when the G-rich repeats considerably expand. (huji.ac.il)
4 ] suggested that microsatellite instability could be used as a biomarker for PD-1 blockers in different tumors (colorectal, endometrial, cervical, esophageal, skin, and breast cancer) and that MSI plays a more significant role in precision medicine. (biomedcentral.com)
While it was originally believed that the size of inherited repeats is the key factor in disease development, it has become clear that somatic instability of these repeats throughout an individual's lifetime strongly contributes to disease onset and progression. (stanford.edu)
To unravel the mechanisms of repeat instability in nondividing cells, we created an experimental system to analyze the mutability of Friedreich's ataxia (GAA)n repeats during chronological aging of quiescent Saccharomyces cerevisiae Unexpectedly, we found that the predominant repeat-mediated mutation in nondividing cells is large-scale deletions encompassing parts, or the entirety, of the repeat and adjacent regions. (stanford.edu)
Altogether, these findings show that the mechanisms and types of (GAA)n repeat instability differ dramatically between dividing and nondividing cells, suggesting that distinct repeat-mediated mutations in terminally differentiated somatic cells might influence Friedreich's ataxia pathogenesis. (stanford.edu)
On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability. (stanford.edu)
We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. (stanford.edu)
Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. (stanford.edu)
We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. (stanford.edu)
We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. (stanford.edu)
Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases? (stanford.edu)
This is an early event in serrated pathway tumourigenesis, and the BRAF V600E has been commonly associated with the CpG island methylator phenotype, microsatellite instability (MSI), and a consistent clinical presentation including a proximal location and predilection for elderly females. (hindawi.com)
Alongside zinc finger nucleases and transcription activator-like effector nuclease (TALEN) proteins, Cas9 is becoming a prominent tool in the field of genome editing. (wikipedia.org)
Cas9 has also been used in the treatment of Hepatitis B through targeting of the ends of certain of long terminal repeats in the Hepatitis B viral genome. (wikipedia.org)
More than half of the human genome is comprised of repetitive elements, including interspersed and tandem repeats, and more than 60 hereditary diseases are caused by the expansion of short tandem repeats (STRs). (ufl.edu)
We previously showed that binding of EWS-FLI1 to GGAA microsatellite repeats in the genome converts these sites into active enhancers," says Miguel Rivera, MD, MGH Department of Pathology and Center for Cancer Research, co-senior author of the report. (toppersonalhealth.com)
Even more-highly repeated sequences - minisatellites, microsatellites and telomeres - may appear as tens or even hundreds of thousands of copies, in aggregate amounting to 15% of the genome. (cilecenter.org)
We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. (stanford.edu)
We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. (stanford.edu)
Mutation1
Project Narrative A microsatellite repeat expansion mutation in the C9orf72 gene is the most common reported cause of familial forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). (neurodegenerationresearch.eu)
Phenotype2
To describe the clinical phenotype and genetic basis of non-syndromic retinitis pigmentosa (RP) in one family and two sporadic cases with biallelic mutations in the transcription factor neural retina leucine zipper ( NRL) . (molvis.org)
A proportion of the BRAF mutant lesions remain as microsatellite stable (MSS), and in contrast to the MSI cancers, they have an aggressive phenotype and correlate with poor patient outcomes. (hindawi.com)
Proteins2
While the molecular basis of this disease (C9-ALS/FTD) remains largely unknown, proposed disease mechanisms include C9orf72 loss of function due to haploinsufficiency, RNA gain of function (GOF) leading to protein sequestration and repeat-associated non-ATG (RAN) translation resulting in the production of toxic C9-RAN dipeptide repeat proteins. (neurodegenerationresearch.eu)
Somatic repeat expansion and/or age-related cellular stress results in titration of GGGGCC and GGCCCC RNA binding proteins followed by nucleocytoplasmic export of these RNAs and translation of highly toxic C9-RAN proteins in the cytoplasm that lead to neurodegeneration. (neurodegenerationresearch.eu)
Factors3
These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. (bvsalud.org)
According to this hypothesis, bidirectional sense and antisense C9orf72 transcription results in the recruitment of cellular factors to repeat expansion RNAs to produce sense and antisense RNA foci that sequester these toxic RNAs in the nucleus. (neurodegenerationresearch.eu)
CTCDOs exhibited a hybrid epithelial-mesenchymal transition (EMT) state and an increased expression of stemness-associated markers including the two homeobox transcription factors Goosecoid and Pancreatic Duodenal Homeobox Gene-1 (PDX1), which were also detected in CTCs from CRC patients. (biomedcentral.com)
Alleles1
Using human embryonic stem cells with wild-type and repeat expanded alleles in the FMR1 (CGGs) and C9orf72 (GGGGCCs) genes, we show that these loci constitute preferential sites (hotspots) for DNA unpairing. (huji.ac.il)
Nucleotides2
CRISPR loci are composed of short, palindromic repeats that occur at regular intervals composed of alternate CRISPR repeats and variable CRISPR spacers between 24 and 48 nucleotides long. (wikipedia.org)
The researchers focused on GGAA microsatellites-repeats of the nucleotides guanine and adenine-that are usually inactive but in Ewing sarcoma are bound and activated by EWS-FLI1. (toppersonalhealth.com)
Tandem3
Cell-type-specific dysregulation of RNA alternative splicing in short tandem repeat mouse knockin models of myotonic dystrophy. (ufl.edu)
Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. (bvsalud.org)
Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. (stanford.edu)
Motifs1
The white shark transcriptome also contained 8,404 microsatellites (dinucleotide, trinucleotide, or tetranucleotide motifs ≥ five perfect repeats). (sharkyear.com)
Repetitive2
A 2014 Cancer Cell study led by Rivera and Bradley Bernstein, MD, Ph.D., also of MGH Pathology and the Center for Cancer Research, found that EWS-FLI1 had two properties that could lead to tumor growth: conversion of microsatellite repeats-repetitive DNA elements commonly found in the genome-into active enhancers that stimulate the expression of other genes and repression of other factors that regulate gene transcription. (toppersonalhealth.com)
Nearly 50 hereditary diseases result from the inheritance of abnormally long repetitive DNA microsatellites. (stanford.edu)
Tumor3
Now we have used new epigenome editing tools to turn off individual microsatellites and demonstrate that they have important functions in controlling the expression of nearby genes that are critical for tumor growth. (toppersonalhealth.com)
The current study was designed to directly test the links between microsatellite activation by EWS-FLI1, the expression of cancer-associated genes and tumor growth. (toppersonalhealth.com)
The investigators used a novel CRISPR-based system to bring a repressor module to sites adjacent to the GGAA microsatellites in Ewing sarcoma cells, which markedly reduced expression of nearby genes believed to stimulate tumor growth. (toppersonalhealth.com)
Cancer1
In contrast, repression of GGAA repeats in cancer cells that did not express the fusion protein had no effect on gene expression. (toppersonalhealth.com)
Expansion diseases1
Based on our prior studies on other microsatellite expansion diseases, this proposal is designed to test our sequestration failure hypothesis, which integrates RNA and RAN gain of function mechanisms. (neurodegenerationresearch.eu)
Expansions2
Repeat expansions accrue during chronological aging as well-particularly in the absence of MMR-induced DSBs. (stanford.edu)
In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. (stanford.edu)
Stable1
The remaining BRAF mutant cancers that do not methylate MLH1 to develop MSI stay as microsatellite stable (MSS). (hindawi.com)
Markers3
Pseudomolecules as well as unmapped scaffolds were used for the bulk mining of SSR markers and for the construction of the first globe artichoke microsatellite marker database. (researchgate.net)
scolymus) has been used to catalog the genome's content of simple sequence repeat (SSR) markers. (researchgate.net)
In genetic diversity studies, the most frequently used markers are microsatellites. (intechopen.com)
Gene2
Project Summary The expansion of a microsatellite GGGGCC repeat in the C9orf72 gene has been linked to both familial and sporadic forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). (neurodegenerationresearch.eu)
We also observed repeat-mediated gene conversions as a result of DSB repair via ectopic homologous recombination during chronological aging. (stanford.edu)
Loci1
Our study thus takes one more step toward the identification of dynamic, unconventional DNA structures across the G-rich repeats at FMR1 and C9orf72 disease-associated loci. (huji.ac.il)
Other regions contain binding sites for ligands responsible for the regulation of transcription. (cilecenter.org)
Factor1
Finally, silencing a specific repeat known to regulate expression of SOX2, a transcription factor that acts as an oncogene, led to a significant decrease in the size of Ewing sarcoma tumors in mice. (toppersonalhealth.com)
Long1
Cas9 has been shown to suppress the expression of the long terminal repeats in HIV-1. (wikipedia.org)
Found1
A complex CA-repeat was isolated from the BAC clones and was found to be polymorphic in German shepherd dogs. (nih.gov)
Island1
In alternative models, CpG island density, transcription start site density, H3K4me1 coverage, and mononucleotide microsatellite coverage are significant predictors. (psu.edu)
Repair1
These deletions are caused by breakage at the repeat mediated by mismatch repair (MMR) complexes MutSβ and MutLα and DNA endonuclease Rad1, followed by end-resection by Exo1 and repair of the resulting double-strand breaks (DSBs) via nonhomologous end joining. (stanford.edu)
Models1
In our optimal models (having highest explanatory power), aCFSs are predominantly located in G-negative chromosomal bands and away from centromeres, are enriched in Alu repeats, and have high DNA flexibility. (psu.edu)