The Experts below are selected from a list of 7209 Experts worldwide ranked by ideXlab platform
Yuan Liu - One of the best experts on this subject based on the ideXlab platform.
-
r loops promote Trinucleotide Repeat deletion through dna base excision repair enzymatic activities
Journal of Biological Chemistry, 2020Co-Authors: Eduardo E. Laverde, Yanhao Lai, Lata Balakrishnan, Catherine H Freudenreich, Fenfei Leng, Yuan LiuAbstract:Trinucleotide Repeat (TNR) expansion and deletion are responsible for over 40 neurodegenerative diseases and associated with cancer. TNRs can undergo somatic instability that is mediated by DNA damage and repair and gene transcription. Recent studies have pointed toward a role for R-loops in causing TNR expansion and deletion, and it has been shown that base excision repair (BER) can result in CAG Repeat deletion from R-loops in yeast. However, it remains unknown how BER in R-loops can mediate TNR instability. In this study, using biochemical approaches, we examined BER enzymatic activities and their influence on TNR R-loops. We found that AP endonuclease 1 incised an abasic site on the nontemplate strand of a TNR R-loop, creating a double-flap intermediate containing an RNA:DNA hybrid that subsequently inhibited polymerase β (pol β) synthesis of TNRs. This stimulated flap endonuclease 1 (FEN1) cleavage of TNRs engaged in an R-loop. Moreover, we showed that FEN1 also efficiently cleaved the RNA strand, facilitating pol β loop/hairpin bypass synthesis and the resolution of TNR R-loops through BER. Consequently, this resulted in fewer TNRs synthesized by pol β than those removed by FEN1, thereby leading to Repeat deletion. Our results indicate that TNR R-loops preferentially lead to Repeat deletion during BER by disrupting the balance between the addition and removal of TNRs. Our discoveries open a new avenue for the treatment and prevention of Repeat expansion diseases and cancer.
-
proliferating cell nuclear antigen prevents Trinucleotide Repeat expansions by promoting Repeat deletion and hairpin removal
DNA Repair, 2016Co-Authors: Jill M. Beaver, Yanhao Lai, Shantell J Rolle, Yuan LiuAbstract:DNA base lesions and base excision repair (BER) within Trinucleotide Repeat (TNR) tracts modulate Repeat instability through the coordination among the key BER enzymes DNA polymerase β, flap endonuclease 1 (FEN1) and DNA ligase I (LIG I). However, it remains unknown whether BER cofactors can also alter TNR stability. In this study, we discovered that proliferating cell nuclear antigen (PCNA), a cofactor of BER, promoted CAG Repeat deletion and removal of a CAG Repeat hairpin during BER in a duplex CAG Repeat tract and CAG hairpin loop, respectively. We showed that PCNA stimulated LIG I activity on a nick across a small template loop during BER in a duplex (CAG)20 Repeat tract promoting small Repeat deletions. Surprisingly, we found that during BER in a hairpin loop, PCNA promoted reannealing of the upstream flap of a double-flap intermediate, thereby facilitating the formation of a downstream flap and stimulating FEN1 cleavage activity and hairpin removal. Our results indicate that PCNA plays a critical role in preventing CAG Repeat expansions by modulating the structures of dynamic DNA via cooperation with BER enzymes. We provide the first evidence that PCNA prevents CAG Repeat expansions during BER by promoting CAG Repeat deletion and removal of a TNR hairpin.
-
crosstalk between msh2 msh3 and polβ promotes Trinucleotide Repeat expansion during base excision repair
Nature Communications, 2016Co-Authors: Yanhao Lai, Jill M. Beaver, Helen Budworth, Nelson L S Chan, Zunzhen Zhang, Cynthia T Mcmurray, Yuan LiuAbstract:Studies in knockout mice provide evidence that MSH2-MSH3 and the BER machinery promote Trinucleotide Repeat (TNR) expansion, yet how these two different repair pathways cause the mutation is unknown. Here we report the first molecular crosstalk mechanism, in which MSH2-MSH3 is used as a component of the BER machinery to cause expansion. On its own, pol β fails to copy TNRs during DNA synthesis, and bypasses them on the template strand to cause deletion. Remarkably, MSH2-MSH3 not only stimulates pol β to copy through the Repeats but also enhances formation of the flap precursor for expansion. Our results provide direct evidence that MMR and BER, operating together, form a novel hybrid pathway that changes the outcome of TNR instability from deletion to expansion during the removal of oxidized bases. We propose that cells implement crosstalk strategies and share machinery when a canonical pathway is ineffective in removing a difficult lesion.
-
AP endonuclease 1 prevents Trinucleotide Repeat expansion via a novel mechanism during base excision repair
Nucleic acids research, 2015Co-Authors: Jill M. Beaver, Yanhao Lai, Astrid H. Casin, Eduardo E. Laverde, Yuan LiuAbstract:Base excision repair (BER) of an oxidized base within a Trinucleotide Repeat (TNR) tract can lead to TNR expansions that are associated with over 40 human neurodegenerative diseases. This occurs as a result of DNA secondary structures such as hairpins formed during repair. We have previously shown that BER in a TNR hairpin loop can lead to removal of the hairpin, attenuating or preventing TNR expansions. Here, we further provide the first evidence that AP endonuclease 1 (APE1) prevented TNR expansions via its 3′-5′ exonuclease activity and stimulatory effect on DNA ligation during BER in a hairpin loop. Coordinating with flap endonuclease 1, the APE1 3′-5′ exonuclease activity cleaves the annealed upstream 3′-flap of a double-flap intermediate resulting from 5′-incision of an abasic site in the hairpin loop. Furthermore, APE1 stimulated DNA ligase I to resolve a long double-flap intermediate, thereby promoting hairpin removal and preventing TNR expansions.
-
DNA base excision repair: a mechanism of Trinucleotide Repeat expansion.
Trends in biochemical sciences, 2012Co-Authors: Yuan Liu, Samuel H. WilsonAbstract:The expansion of Trinucleotide Repeat (TNR) sequences in human DNA is considered to be a key factor in the pathogenesis of more than 40 neurodegenerative diseases. TNR expansion occurs during DNA replication and also, as suggested by recent studies, during the repair of DNA lesions produced by oxidative stress. In particular, the oxidized guanine base 8-oxoguanine within sequences containing CAG Repeats may induce formation of pro-expansion intermediates through strand slippage during DNA base excision repair (BER). In this article, we describe how oxidized DNA lesions are repaired by BER and discuss the importance of the coordinated activities of the key repair enzymes, such as DNA polymerase β, flap endonuclease 1 (FEN1) and DNA ligase, in preventing strand slippage and TNR expansion.
Kenneth H. Fischbeck - One of the best experts on this subject based on the ideXlab platform.
-
stability of an expanded Trinucleotide Repeat in the androgen receptor gene in transgenic mice
Nature Genetics, 1995Co-Authors: Peter M Bingham, Marion O Scott, S Wang, Michael J Mcphaul, Elizabeth M Wilson, James Y Garbern, Diane E Merry, Kenneth H. FischbeckAbstract:The expansion of Trinucleotide Repeat sequences underlies a number of hereditary neurological disorders. To study the stability of a Trinucleotide Repeat and to develop an animal model of one of these disorders, spinal and bulbar muscular atrophy (SBMA), we have generated transgenic mice carrying either the normal or expanded Repeat human androgen receptor (AR) gene. Unlike the disease allele in humans, the AR cDNA containing the expanded Repeat in transgenic mice showed no change in Repeat length with transmission. Expression of the SBMA AR was found in transgenic mice, but at a lower level than normal endogenous expression. The lack of a physiological pattern of expression may explain why no phenotypic effects of the transgene were observed.
-
Trinucleotide Repeat expansion in neurological disease
Annals of neurology, 1994Co-Authors: Albert R. La Spada, Henry L. Paulson, Kenneth H. FischbeckAbstract:Abstract Expansion of Trinucleotide Repeats is now recognized as a major cause of neurological disease. At least seven disorders result from Trinucleotide Repeat expansion: X-linked spinal and bulbar muscular atrophy (SBMA), two fragile X syndromes of mental retardation (FRAXA and FRAXE), myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). The expanded Trinucleotide Repeats are unstable, and the phenomenon of anticipation, i.e., worsening of disease phenotype over successive generations, correlates with increasing expansion size. In this review, we compare the clinical and molecular features of the Trinucleotide Repeat diseases, which may be classified into two types. Fragile X and myotonic dystrophy are multisystem disorders usually associated with large expansions of untranslated Repeats, while the four neurodegenerative disorders, SBMA, Huntington's disease, SCA1, and DRPLA, are caused by smaller expansions of CAG Repeats within the protein coding portion of the gene. CAG Repeats encode polyglutamine tracts. Polyglutamine tract expansion thus appears to be a common mechanism of inherited neurodegenerative disease. Although polyglutamine tract lengthening presumably has a toxic gain of function effect in the CAG Trinucleotide Repeat disorders, the basis of this neuronal toxicity remains unknown.
-
meiotic stability and genotype phenotype correlation of the Trinucleotide Repeat in x linked spinal and bulbar muscular atrophy
Nature Genetics, 1992Co-Authors: D B Roling, A E Harding, C L Warner, R Spiegel, Irena Hausmanowapetrusewicz, W C Yee, Kenneth H. FischbeckAbstract:Expansion of the Trinucleotide Repeat (CAG)n in the first exon of the androgen receptor gene is associated with a rare motor neuron disorder, X-linked spinal and bulbar muscular atrophy. We have found that expanded (CAG)n alleles undergo alteration in length when transmitted from parent to offspring. Of 45 meioses examined, 12 (27%) demonstrated a change in CAG Repeat number. Both expansions and contractions were observed, although their magnitude was small. There was a greater rate of instability in male meiosis than in female meiosis. We also found evidence for a correlation between disease severity and CAG Repeat length, but other factors seem to contribute to the phenotypic variability in this disorder.
Guyfranck Richard - One of the best experts on this subject based on the ideXlab platform.
-
Trinucleotide Repeat instability during double-strand break repair: from mechanisms to gene therapy
Current Genetics, 2019Co-Authors: Valentine Mosbach, Lucie Poggi, Guyfranck RichardAbstract:Trinucleotide Repeats are a particular class of microsatellites whose large expansions are responsible for at least two dozen human neurological and developmental disorders. Slippage of the two complementary DNA strands during replication, homologous recombination or DNA repair is generally accepted as a mechanism leading to Repeat length changes, creating expansions and contractions of the Repeat tract. The present review focuses on recent developments on double-strand break repair involving Trinucleotide Repeat tracts. Experimental evidences in model organisms show that gene conversion and break-induced replication may lead to large Repeat tract expansions, while frequent contractions occur either by single-strand annealing between Repeat ends or by gene conversion, triggering near-complete contraction of the Repeat tract. In the second part of this review, different therapeutic approaches using highly specific single- or double-strand endonucleases targeted to Trinucleotide Repeat loci are compared. Relative efficacies and specificities of these nucleases will be discussed, as well as their potential strengths and weaknesses for possible future gene therapy of these dramatic disorders.
-
highly specific contractions of a single cag ctg Trinucleotide Repeat by talen in yeast
PLOS ONE, 2014Co-Authors: Guyfranck Richard, David Viterbo, Varun Khanna, Valentine MosbachAbstract:Trinucleotide Repeat expansions are responsible for more than two dozens severe neurological disorders in humans. A double-strand break between two short CAG/CTG Trinucleotide Repeats was formerly shown to induce a high frequency of Repeat contractions in yeast. Here, using a dedicated TALEN, we show that induction of a double-strand break into a CAG/CTG Trinucleotide Repeat in heterozygous yeast diploid cells results in gene conversion of the Repeat tract with near 100% efficacy, deleting the Repeat tract. Induction of the same TALEN in homozygous yeast diploids leads to contractions of both Repeats to a final length of 3–13 triplets, with 100% efficacy in cells that survived the double-strand breaks. Whole-genome sequencing of surviving yeast cells shows that the TALEN does not increase mutation rate. No other CAG/CTG Repeat of the yeast genome showed any length alteration or mutation. No large genomic rearrangement such as aneuploidy, segmental duplication or translocation was detected. It is the first demonstration that induction of a TALEN in an eukaryotic cell leads to shortening of Trinucleotide Repeat tracts to lengths below pathological thresholds in humans, with 100% efficacy and very high specificity.
Arne Klungland - One of the best experts on this subject based on the ideXlab platform.
-
neil1 is a genetic modifier of somatic and germline cag Trinucleotide Repeat instability in r6 1 mice
Human Molecular Genetics, 2012Co-Authors: Linda Mollersen, Alexander D Rowe, Jennifer L Illuzzi, Gunn A Hildrestrand, Katharina J Gerhold, Linda Tveteras, Anja Bjolgerud, David M Wilson, Magnar Bjoras, Arne KlunglandAbstract:Huntington's disease (HD) is a progressive neurodegenerative disorder caused by Trinucleotide Repeat (TNR) expansions. We show here that somatic TNR expansions are significantly reduced in several organs of R6/1 mice lacking exon 2 of Nei-like 1 (Neil1) (R
-
neil1 is a genetic modifier of somatic and germline cag Trinucleotide Repeat instability in r6 1 mice
Human Molecular Genetics, 2012Co-Authors: Linda Mollersen, Alexander D Rowe, Jennifer L Illuzzi, Gunn A Hildrestrand, Katharina J Gerhold, Linda Tveteras, Anja Bjolgerud, David M Wilson, Magnar Bjoras, Arne KlunglandAbstract:Huntington's disease (HD) is a progressive neurodegenerative disorder caused by Trinucleotide Repeat (TNR) expansions. We show here that somatic TNR expansions are significantly reduced in several organs of R6/1 mice lacking exon 2 of Nei-like 1 (Neil1) (R6/1/Neil1(-/-)), when compared with R6/1/Neil1(+/+) mice. Somatic TNR expansion is measured by two different methods, namely mean Repeat change and instability index. Reduced somatic expansions are more pronounced in male R6/1/Neil1(-/-) mice, although expansions are also significantly reduced in brain regions of female R6/1/Neil1(-/-) mice. In addition, we show that the lack of functional Neil1 significantly reduces germline expansion in R6/1 male mice. In vitro, purified human NEIL1 protein binds and excises 5-hydroxycytosine in duplex DNA more efficiently than in hairpin substrates. NEIL1 excision of cytosine-derived oxidative lesions could therefore be involved in initiating the process of TNR expansion, although other DNA modifications might also contribute. Altogether, these results imply that Neil1 contributes to germline and somatic HD CAG Repeat expansion.
Malinda L. Butz - One of the best experts on this subject based on the ideXlab platform.
-
Effect of Trinucleotide Repeat expansion on the expression of TCF4 mRNA in fuchs’ endothelial corneal dystrophy
Investigative Opthalmology & Visual Science, 2019Co-Authors: Naoki Okumura, Derek J Blake, Masakazu Nakano, Kei Tashiro, Kengo Yoshii, Ross A. Aleff, Malinda L. Butz, Ryosuke Hayashi, Takahiko Sato, W. Edward HighsmithAbstract:Purpose: CTG Trinucleotide Repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. Methods: Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR Repeat length in TCF4 was determined by short tandem Repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. Results: The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80%) harbored CTG Trinucleotide Repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. Conclusions: Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD.
-
Trinucleotide Repeat Expansion in the TCF4 Gene in Fuchs' Endothelial Corneal Dystrophy in Japanese.
Investigative ophthalmology & visual science, 2015Co-Authors: Masakazu Nakano, Naoki Okumura, Kengo Yoshii, Ross A. Aleff, Hiroko Nakagawa, Noriko Koizumi, Yoko Ikeda, Morio Ueno, Hiroko Adachi, Malinda L. ButzAbstract:PURPOSE The purpose of this study was to evaluate the association between the intronic expansion of a Trinucleotide Repeat (TNR) in the TCF4 gene and Fuchs' endothelial corneal dystrophy (FECD) in a Japanese population. METHODS Forty-seven Japanese FECD patients and 96 age-matched controls were recruited. FECD patients and controls were examined by slit-lamp and noncontact specular microscopy. The Repeat length was determined by direct sequencing and short tandem Repeat assay of PCR-amplified DNA and Southern blotting of unamplified DNA. RESULTS A TNR expansion, defined as >50 CTG Repeats in the TCF4 gene was identified in 12 of 47 FECD cases (26%) and 0 of 96 controls (0%; P < 0.001). Sensitivity and specificity in this study were 26% and 100%, respectively. The clinical characteristics of FECD patients with TNR expansion were not distinct from those without TNR expansion. CONCLUSIONS These findings show for the first time in a Japanese population the association of the TNR expansion in TCF4 with FECD. In contrast to Caucasian cohorts in whom the TNR expansion is present in most patients with FECD, a CTG expansion is present in a minority of Japanese subjects, indicating other genetic variants as common causes of phenotypically identical disease in this population.
-
A common Trinucleotide Repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts Fuchs corneal dystrophy.
PloS one, 2012Co-Authors: Eric D. Wieben, Ross A. Aleff, Malinda L. Butz, W. Edward Highsmith, Nirubol Tosakulwong, Albert O. Edwards, Keith H. BaratzAbstract:Fuchs endothelial corneal dystrophy (FECD) is a common, familial disease of the corneal endothelium and is the leading indication for corneal transplantation. Variation in the transcription factor 4 (TCF4) gene has been identified as a major contributor to the disease. We tested for an association between an intronic TGC Trinucleotide Repeat in TCF4 and FECD by determining Repeat length in 66 affected participants with severe FECD and 63 participants with normal corneas in a 3-stage discovery/replication/validation study. PCR primers flanking the TGC Repeat were used to amplify leukocyte-derived genomic DNA. Repeat length was determined by direct sequencing, short tandem Repeat (STR) assay and Southern blotting. Genomic Southern blots were used to evaluate samples for which only a single allele was identified by STR analysis. Compiling data for 3 arms of the study, a TGC Repeat length >50 was present in 79% of FECD cases and in 3% of normal controls cases (p 50 TGC Repeats, 13 (20%) had 50 Repeats, 60 (95%) had 50 TGC Repeats identifying FECD in this patient cohort was 79% and 96%, respectively Expanded TGC Repeat was more specific for FECD cases than the previously identified, highly associated, single nucleotide polymorphism, rs613872 (specificity = 79%). The TGC Trinucleotide Repeat expansion in TCF4 is strongly associated with FECD, and a Repeat length >50 is highly specific for the disease This association suggests that Trinucleotide expansion may play a pathogenic role in the majority of FECD cases and is a predictor of disease risk.
