The Experts below are selected from a list of 795 Experts worldwide ranked by ideXlab platform
Jennifer L. Gerton - One of the best experts on this subject based on the ideXlab platform.
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Scientific Report The cohesin acetyltransferase Eco1 coordinates rDNA replication and transcription
2016Co-Authors: Kenneth K Lee, Tania Bose, Bethany Harris, Bo Xiong, Anita Saraf, Gaye Hattem, Laurence Florens, Chris Seidel, Jennifer L. GertonAbstract:Eco1 is the acetyltransferase that establishes sister-chromatid cohesion during DNA replication. A budding yeast strain with an eco1 mutation that genocopies Roberts Syndrome has reduced ribosomal DNA (rDNA) transcription and a transcriptional signature of starvation. We show that deleting FOB1—a gene that encodes a replication fork-blocking protein specific for the rDNA region— rescues rRNA production and partially rescues transcription genome-wide. Further studies show that deletion of FOB1 corrects the genome-wide replication defects, nucleolar structure, and rDNA segregation that occur in the eco1 mutant. Our study high-lights that the presence of cohesin at the rDNA locus has a central role in controlling global DNA replication and gene expression
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improved transcription and translation with l leucine stimulation of mtorc1 in Roberts Syndrome
BMC Genomics, 2016Co-Authors: Madelaine Gogol, Jennifer L. Gerton, Karin GaudenzAbstract:Roberts Syndrome (RBS) is a human developmental disorder caused by mutations in the cohesin acetyltransferase ESCO2. We previously reported that mTORC1 signaling was depressed and overall translation was reduced in RBS cells and zebrafish models for RBS. Treatment of RBS cells and zebrafish RBS models with L-leucine partially rescued mTOR function and protein synthesis, correlating with increased cell division and improved development. In this study, we use RBS cells to model mTORC1 repression and analyze transcription and translation with ribosome profiling to determine gene-level effects of L-leucine. L-leucine treatment partially rescued translational efficiency of ribosomal subunits, translation initiation factors, snoRNA production, and mitochondrial function in RBS cells, consistent with these processes being mTORC1 controlled. In contrast, other genes are differentially expressed independent of L-leucine treatment, including imprinted genes such as H19 and GTL2, miRNAs regulated by GTL2, HOX genes, and genes in nucleolar associated domains. Our study distinguishes between gene expression changes in RBS cells that are TOR dependent and those that are independent. Some of the TOR independent gene expression changes likely reflect the architectural role of cohesin in chromatin looping and gene expression. This study reveals the dramatic rescue effects of L-leucine stimulation of mTORC1 in RBS cells and supports that normal gene expression and translation requires ESCO2 function.
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l leucine partially rescues translational and developmental defects associated with zebrafish models of cornelia de lange Syndrome
Human Molecular Genetics, 2015Co-Authors: Baoshan Xu, Jennifer L. Gerton, Nenja Sowa, Maria E CardenasAbstract:Cohesinopathies are human genetic disorders that include Cornelia de Lange Syndrome (CdLS) and Roberts Syndrome (RBS) and are characterized by defects in limb and craniofacial development as well as mental retardation. The developmental phenotypes of CdLS and other cohesinopathies suggest that mutations in the structure and regulation of the cohesin complex during embryogenesis interfere with gene regulation. In a previous project, we showed that RBS was associated with highly fragmented nucleoli and defects in both ribosome biogenesis and protein translation. l-leucine stimulation of the mTOR pathway partially rescued translation in human RBS cells and development in zebrafish models of RBS. In this study, we investigate protein translation in zebrafish models of CdLS. Our results show that phosphorylation of RPS6 as well as 4E-binding protein 1 (4EBP1) was reduced in nipbla/b, rad21 and smc3-morphant embryos, a pattern indicating reduced translation. Moreover, protein biosynthesis and rRNA production were decreased in the cohesin morphant embryo cells. l-leucine partly rescued protein synthesis and rRNA production in the cohesin morphants and partially restored phosphorylation of RPS6 and 4EBP1. Concomitantly, l-leucine treatment partially improved cohesinopathy embryo development including the formation of craniofacial cartilage. Interestingly, we observed that alpha-ketoisocaproate (α-KIC), which is a keto derivative of leucine, also partially rescued the development of rad21 and nipbla/b morphants by boosting mTOR-dependent translation. In summary, our results suggest that cohesinopathies are caused in part by defective protein synthesis, and stimulation of the mTOR pathway through l-leucine or its metabolite α-KIC can partially rescue development in zebrafish models for CdLS.
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deciphering translational and transcriptional impairment in Roberts Syndrome 1138 6
The FASEB Journal, 2014Co-Authors: Tania Bose, Jennifer L. Gerton, Karin Zueckertgaudenz, Madelaine GogolAbstract:Roberts Syndrome (RBS) is an autosomal recessive disease characterized by prenatal growth retardation caused by mutations in the cohesin acetyltransferase ESCO2 gene. Previously we revealed that mu...
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Roberts Syndrome a deficit in acetylated cohesin leads to nucleolar dysfunction
Rare diseases (Austin Tex.), 2014Co-Authors: Jennifer L. GertonAbstract:All living organisms must go through cycles of replicating their genetic information and then dividing the copies between two new cells. This cyclical process, in cells from bacteria and human alike, requires a protein complex known as cohesin. Cohesin is a structural maintenance of chromosomes (SMC) complex. While bacteria have one form of this complex, yeast have several SMC complexes, and humans have at least a dozen cohesin complexes alone. Therefore the ancient structure and function of SMC complexes has been both conserved and specialized over the course of evolution. These complexes play roles in replication, repair, organization, and segregation of the genome. Mutations in the genes that encode cohesin and its regulatory factors are associated with developmental disorders such as Roberts Syndrome, Cornelia de Lange Syndrome, and cancer. In this review, we focus on how acetylation of cohesin contributes to its function. In Roberts Syndrome, the lack of cohesin acetylation contributes to nucleolar defects and translational inhibition. An understanding of basic SMC complex function will be essential to unraveling the molecular etiology of human diseases associated with defective SMC function.
Peter Wieacker - One of the best experts on this subject based on the ideXlab platform.
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prenatal diagnosis of Roberts Syndrome and detection of an esco2 frameshift mutation in a pakistani family
Prenatal Diagnosis, 2008Co-Authors: Solveig Schulz, Claudia Gerloff, Susanne Ledig, Dorothea Langer, Mariannne Volleth, Katayoon Shirneshan, Peter WieackerAbstract:Objectives We report two siblings with Roberts Syndrome (RBS), and an attempt to delineate the underlying molecular mechanism leading to familial recurrence. Methods Cytogenetic studies and direct sequencing of the ESCO2 gene were carried out in the second affected fetus and the parents. Fetal DNA was obtained from amniocytes after amniocentesis. Parental DNA was obtained from peripheral blood samples. Results Cytogenetic analysis of amniocytes revealed a normal male karyotype in 20 analyzed metaphases and chromosomal aneuploidies in 10 metaphases. All metaphases displayed premature separation of centromeres and puffing of heterochromatic regions near the centromere. A homozygous mutation leading to a frameshift in ESCO2 was identified in the fetal DNA sample. Both parents are heterozygous carriers of the same mutation. Conclusion The present case demonstrates the prenatal diagnosis of RBS associated with a frameshift mutation in ESCO2. Copyright © 2008 John Wiley & Sons, Ltd.
G Andria - One of the best experts on this subject based on the ideXlab platform.
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a mild form of Roberts sc phocomelia Syndrome with asymmetrical reduction of the upper limbs
Clinical Genetics, 2008Co-Authors: Daniela Concolino, D Sperli, R Cinti, P Strisciuglio, G AndriaAbstract:Roberts Syndrome is a rare autosomal recessive condition characterized by growth retardation, cranio-facial abnormalities and symmetrical limb reduction of variable severity. Most patients with Roberts Syndrome show a typical cytogenetic finding known as "Roberts Syndrome effect". We describe a 4-month-old patient with a mild form of this Syndrome, who presented with an asymmetrical reduction of the right upper limb.
Quinten Waisfisz - One of the best experts on this subject based on the ideXlab platform.
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the cellular phenotype of Roberts Syndrome fibroblasts as revealed by ectopic expression of esco2
PLOS ONE, 2009Co-Authors: Petra Van Der Lelij, Anneke B Oostra, Barbara C Godthelp, Wouter Van Zon, Djoke Van Gosliga, Jurgen Steltenpool, Jan De Groot, Rik J Scheper, Rob M F Wolthuis, Quinten WaisfiszAbstract:Cohesion between sister chromatids is essential for faithful chromosome segregation. In budding yeast, the acetyltransferase Eco1/Ctf7 establishes cohesion during DNA replication in S phase and in response to DNA double strand breaks in G2/M phase. In humans two Eco1 orthologs exist: ESCO1 and ESCO2. Both proteins are required for proper sister chromatid cohesion, but their exact function is unclear at present. Since ESCO2 has been identified as the gene defective in the rare autosomal recessive cohesinopathy Roberts Syndrome (RBS), cells from RBS patients can be used to elucidate the role of ESCO2. We investigated for the first time RBS cells in comparison to isogenic controls that stably express V5- or GFP-tagged ESCO2. We show that the sister chromatid cohesion defect in the transfected cell lines is rescued and suggest that ESCO2 is regulated by proteasomal degradation in a cell cycle-dependent manner. In comparison to the corrected cells RBS cells were hypersensitive to the DNA-damaging agents mitomycin C, camptothecin and etoposide, while no particular sensitivity to UV, ionizing radiation, hydroxyurea or aphidicolin was found. The cohesion defect of RBS cells and their hypersensitivity to DNA-damaging agents were not corrected by a patient-derived ESCO2 acetyltransferase mutant (W539G), indicating that the acetyltransferase activity of ESCO2 is essential for its function. In contrast to a previous study on cells from patients with Cornelia de Lange Syndrome, another cohesinopathy, RBS cells failed to exhibit excessive chromosome aberrations after irradiation in G2 phase of the cell cycle. Our results point at an S phase-specific role for ESCO2 in the maintenance of genome stability.
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Roberts Syndrome is caused by mutations in esco2 a human homolog of yeast eco1 that is essential for the establishment of sister chromatid cohesion
Nature Genetics, 2005Co-Authors: Hugo Vega, Quinten Waisfisz, Miriam Gordillo, Norio Sakai, Itaru Yanagihara, Minoru Yamada, Djoke Van Gosliga, Hulya KayseriliAbstract:Roberts Syndrome is an autosomal recessive disorder characterized by craniofacial anomalies, tetraphocomelia and loss of cohesion at heterochromatic regions of centromeres and the Y chromosome. We identified mutations in a new human gene, ESCO2, associated with Roberts Syndrome in 15 kindreds. The ESCO2 protein product is a member of a conserved protein family that is required for the establishment of sister chromatid cohesion during S phase and has putative acetyltransferase activity.
Hugo Vega - One of the best experts on this subject based on the ideXlab platform.
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phenotypic variability in 49 cases of esco2 mutations including novel missense and codon deletion in the acetyltransferase domain correlates with esco2 expression and establishes the clinical criteria for Roberts Syndrome
Journal of Medical Genetics, 2010Co-Authors: Hugo Vega, Hulya Kayserili, M C Gordillo, Alison H Trainer, Moira Crosier, Flemming Skovby, Maria Luisa Giovannucci Uzielli, Rhonda E Schnur, Sylvie Manouvrier, E BlairAbstract:Background Roberts Syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2 , which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations. Genotype–phenotype analysis has been hampered by limited numbers of patients with clinical information available. Objective To provide unpublished clinical data for 31 patients with proven ESCO2 mutations and combine this series with previously reported clinical and mutation data on 18 cases. Methods Genotype–phenotype correlations and functional effects of two novel ESCO2 mutations were analysed. In situ hybridisation on human embryos at Carnegie stages 14, 17 and 21 was performed to study ESCO2 expression during development. Results and conclusions Using the cohort of 49 patients, the clinical criteria for RBS were delineated to include: growth retardation; symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs; characteristic facies with microcephaly. The severity of malformations of the facies correlates with the severity of limb reduction. The occurrence of corneal opacities may be associated with specific mutations. Two new mutations, both in the ESCO2 acetyltransferase domain, are described and their acetylation effects in vitro demonstrated. In situ hybridisation on human embryos showed ESCO2 expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in RBS.
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the molecular mechanism underlying Roberts Syndrome involves loss of esco2 acetyltransferase activity
Human Molecular Genetics, 2008Co-Authors: Hugo Vega, Norio Sakai, M C Gordillo, Alison H Trainer, Fajian Hou, Ricardo Luque, Hulya KayseriliAbstract:Roberts Syndrome/SC phocomelia (RBS) is an autosomal recessive disorder with growth retardation, craniofacial abnormalities and limb reduction. Cellular alterations in RBS include lack of cohesion at the heterochromatic regions around centromeres and the long arm of the Y chromosome, reduced growth capacity, and hypersensitivity to DNA damaging agents. RBS is caused by mutations in ESCO2, which encodes a protein belonging to the highly conserved Eco1/Ctf7 family of acetyltransferases that is involved in regulating sister chromatid cohesion. We identified 10 new mutations expanding the number to 26 known ESCO2 mutations. We observed that these mutations result in complete or partial loss of the acetyltransferase domain except for the only missense mutation that occurs in this domain (c.1615T>G, W539G). To investigate the mechanism underlying RBS, we analyzed ESCO2 mutations for their effect on enzymatic activity and cellular phenotype. We found that ESCO2 W539G results in loss of autoacetyltransferase activity. The cellular phenotype produced by this mutation causes cohesion defects, proliferation capacity reduction and mitomycin C sensitivity equivalent to those produced by frameshift and nonsense mutations associated with decreased levels of mRNA and absence of protein. We found decreased proliferation capacity in RBS cell lines associated with cell death, but not with increased cell cycle duration, which could be a factor in the development of phocomelia and cleft palate in RBS. In summary, we provide the first evidence that loss of acetyltransferase activity contributes to the pathogenesis of RBS, underscoring the essential role of the enzymatic activity of the Eco1p family of proteins.
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Roberts Syndrome is caused by mutations in esco2 a human homolog of yeast eco1 that is essential for the establishment of sister chromatid cohesion
Nature Genetics, 2005Co-Authors: Hugo Vega, Quinten Waisfisz, Miriam Gordillo, Norio Sakai, Itaru Yanagihara, Minoru Yamada, Djoke Van Gosliga, Hulya KayseriliAbstract:Roberts Syndrome is an autosomal recessive disorder characterized by craniofacial anomalies, tetraphocomelia and loss of cohesion at heterochromatic regions of centromeres and the Y chromosome. We identified mutations in a new human gene, ESCO2, associated with Roberts Syndrome in 15 kindreds. The ESCO2 protein product is a member of a conserved protein family that is required for the establishment of sister chromatid cohesion during S phase and has putative acetyltransferase activity.
