Homo sapiens
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PROVIDER: PRJNA359144 | ENA |
REPOSITORIES: ENA
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Project description:DNA Inverted Repeats as an At-risk Motif for Palindromic Gene Amplification
| PRJNA359143 | ENA
Project description:<p>DNA Inverted Repeats as an At-risk Motif for Palindromic Gene Amplificatio defines oncogene amplification that is configured as a series of inverted duplications (palindromic gene amplification). There are several, recurrently amplified oncogenes throughout the human genome. However, it remains unclear whether this recurrent amplification is solely a manifestation of increased fitness resulting from random amplification mechanisms, or if genomic locus-specific amplification mechanism plays a role. </p> <p>In this study, we show that the ERBB2 oncogene at 17q12 is susceptible to palindromic gene amplification in HER2-positive breast tumors. We investigated eight tumors in this study, of which five tumors were HER2-positive, and three tumors were HER2-negative. HER2-status was determined by clinical FISH tests. We applied three genomic approaches to investigate the amplification mechanism: (1) copy number analysis by array-CGH on the Affymetrix SNP6.0 platform (8 files), (2) sequencing of DNA libraries enriched with tumor-derived palindromic DNA (Genome-wide Analysis of Palindrome Formation, GAPF-seq) (8 files) and (3) unbiased whole genome sequencing (WGS) (1 file). These molecular data is made available in the dbGaP. </p> <p>Genomic studies using tumor DNA was approved under the Internal Institutional Review Board at the Cleveland Clinic (IRB07-136: EXEMPT: Chromosome Breakage and DNA Palindrome Formation). Specimens were obtained and methods were carried out under the auspices of IRB 7881 (Evaluation of Genetic and Molecular Markers in Patients with Breast Cancer). All patients consented to allow their cancer specimens to be used by researchers in an anonymized fashion. The consent form indicates that publication will take place without identifiers to protect the identity of any specific individual.</p> <p>We observed significant and enrichment of palindromic DNA within amplified ERBB2 genomic segments in four out of five HER2-positive tumors. None of three HER2-negative tumors showed such enrichment. Palindromic DNA was particularly enriched at amplification peaks and boundaries between amplified and normal copy-number regions. Thus, palindromic gene amplification shaped the amplified ERBB2 locus. The moderate enrichment of palindromic DNA throughout the amplified segments leads us to propose that the ERBB2 locus is amplified through a mechanism that repeatedly generates palindromic DNA, such as Breakage-Fusion-Bridge cycles. Our results reveal a potential interaction between local genomic environments and gene amplification mechanisms. </p> <p>This study is published under the title "Palindromic amplification of the ERBB2 oncogene in primary HER2-positive breast tumors" <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=28211519" target="_blank">(PMID:28211519)</a>. </p>
| phs001261 | dbGaP
Project description:Amplification of large chromosomal regions (gene amplification) is a common somatic alteration in human cancer cells and often is associated with advanced disease. A critical event initiating gene amplification is a DNA double strand break (DSB), which is immediately followed by the formation of a large DNA palindrome. Large DNA palindromes are frequent and non-randomly distributed in the genomes of cancer cells and facilitate further increase in copy number. Although the importance of the formation of large DNA palindromes as a very early event in gene amplification is widely recognized, it is not known 1) how a DSB is resolved to form a large DNA palindrome; and 2) whether any local DNA structure determines the location of large DNA palindromes. We show here that intra-strand annealing following a DNA double-strand break leads to the formation of large DNA palindromes and that DNA inverted repeats in the genome determines the efficiency of this event. Furthermore, in human Colo320DM cancer cells, a DNA inverted repeat in the genome marks the border between amplified and non-amplified DNA. Therefore, an early step of gene amplification is a regulated process that is facilitated by DNA inverted repeats in the genome. Keywords: cancer vs. normal sample comparison
2007-03-01 | GSE6274 | GEO
Project description:Amplification of large chromosomal regions (gene amplification) is a common somatic alteration in human cancer cells and often is associated with advanced disease. A critical event initiating gene amplification is a DNA double strand break (DSB), which is immediately followed by the formation of a large DNA palindrome. Large DNA palindromes are frequent and non-randomly distributed in the genomes of cancer cells and facilitate further increase in copy number. Although the importance of the formation of large DNA palindromes as a very early event in gene amplification is widely recognized, it is not known 1) how a DSB is resolved to form a large DNA palindrome; and 2) whether any local DNA structure determines the location of large DNA palindromes. We show here that intra-strand annealing following a DNA double-strand break leads to the formation of large DNA palindromes and that DNA inverted repeats in the genome determines the efficiency of this event. Furthermore, in human Colo320DM cancer cells, a DNA inverted repeat in the genome marks the border between amplified and non-amplified DNA. Therefore, an early step of gene amplification is a regulated process that is facilitated by DNA inverted repeats in the genome. Experiment Overall Design: Genomic DNA samples from HFF2 and Colo320DM cells were collected and taken through the GAPF procedure. Their GAPF profiles were analyzed using Affymetrix HGU 133A arrays, and the differentially hybridized genes were determined to be significant according to a FDR<0.05
2008-06-14 | E-GEOD-6274 | biostudies-arrayexpress
Project description:Gene expression profiling of immortalized human mesenchymal stem cells with hTERT/E6/E7 transfected MSCs. hTERT may change gene expression in MSCs. Goal was to determine the gene expressions of immortalized MSCs.
2010-09-25 | GSE24338 | GEO
Project description:Origin-Dependent Inverted-Repeat Amplification: Tests of a Model for Inverted DNA Amplification
| PRJNA300521 | ENA
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:SPO11-promoted DNA double-strand breaks (DSBs) formation is a crucial step for meiotic recombination, and it is indispensable to detect the broken DNA ends accurately for dissecting the molecular mechanisms behind. Here, we report a novel technique, named DEtail-seq (DNA End tailing followed by sequencing), that can directly and quantitatively capture the meiotic DSB 3’ overhang hotspots at single-nucleotide resolution.
2023-01-08 | GSE154227 | GEO
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:As the evolution of miRNA genes has been found to be one of the important factors in formation of the modern type of man, we performed a comparative analysis of the evolution of miRNA genes in two archaic hominines, Homo sapiens neanderthalensis and Homo sapiens denisova, and elucidated the expression of their target mRNAs in bain.A comparative analysis of the genomes of primates, including species in the genus Homo, identified a group of miRNA genes having fixed substitutions with important implications for the evolution of Homo sapiens neanderthalensis and Homo sapiens denisova. The mRNAs targeted by miRNAs with mutations specific for Homo sapiens denisova exhibited enhanced expression during postnatal brain development in modern humans. By contrast, the expression of mRNAs targeted by miRNAs bearing variations specific for Homo sapiens neanderthalensis was shown to be enhanced in prenatal brain development.Our results highlight the importance of changes in miRNA gene sequences in the course of Homo sapiens denisova and Homo sapiens neanderthalensis evolution. The genetic alterations of miRNAs regulating the spatiotemporal expression of multiple genes in the prenatal and postnatal brain may contribute to the progressive evolution of brain function, which is consistent with the observations of fine technical and typological properties of tools and decorative items reported from archaeological Denisovan sites. The data also suggest that differential spatial-temporal regulation of gene products promoted by the subspecies-specific mutations in the miRNA genes might have occurred in the brains of Homo sapiens denisova and Homo sapiens neanderthalensis, potentially contributing to the cultural differences between these two archaic hominines.
| S-EPMC4686780 | biostudies-literature