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https://www.readbyqxmd.com/read/28549257/human-somatic-cells-deficient-for-rad52-are-impaired-for-viral-integration-and-compromised-for-most-aspects-of-homology-directed-repair
#1
Yinan Kan, Nizar N Batada, Eric A Hendrickson
Homology-directed repair (HDR) maintains genomic integrity by eliminating lesions such as DNA double-strand breaks (DSBs), interstrand crosslinks (ICLs) and stalled replication forks and thus a deficiency in HDR is associated with genomic instability and cancer predisposition. The mechanism of HDR is best understood and most rigorously characterized in yeast. The inactivation of the fungal radiation sensitive 52 (RAD52) gene, which has both recombination mediator and single-strand annealing (SSA) activities in vitro, leads to severe HDR defects in vivo...
May 10, 2017: DNA Repair
https://www.readbyqxmd.com/read/28542371/whole-genome-sequencing-of-spermatocytic-tumors-provides-insights-into-the-mutational-processes-operating-in-the-male-germline
#2
Eleni Giannoulatou, Geoffrey J Maher, Zhihao Ding, Ad J M Gillis, Lambert C J Dorssers, Alexander Hoischen, Ewa Rajpert-De Meyts, Gilean McVean, Andrew O M Wilkie, Leendert H J Looijenga, Anne Goriely
Adult male germline stem cells (spermatogonia) proliferate by mitosis and, after puberty, generate spermatocytes that undertake meiosis to produce haploid spermatozoa. Germ cells are under evolutionary constraint to curtail mutations and maintain genome integrity. Despite constant turnover, spermatogonia very rarely form tumors, so-called spermatocytic tumors (SpT). In line with the previous identification of FGFR3 and HRAS selfish mutations in a subset of cases, candidate gene screening of 29 SpTs identified an oncogenic NRAS mutation in two cases...
2017: PloS One
https://www.readbyqxmd.com/read/28541389/cell-cycle-dependent-control-of-homologous-recombination
#3
Xin Zhao, Chengwen Wei, Jingjing Li, Poyuan Xing, Jingyao Li, Sihao Zheng, Xuefeng Chen
DNA double-strand breaks (DSBs) are among the most deleterious type of DNA lesions threatening genome integrity. Homologous recombination (HR) and non-homologous end joining (NHEJ) are two major pathways to repair DSBs. HR requires a homologous template to direct DNA repair, and is generally recognized as a high-fidelity pathway. In contrast, NHEJ directly seals broken ends, but the repair product is often accompanied by sequence alterations. The choice of repair pathways is strictly controlled by the cell cycle...
May 25, 2017: Acta Biochimica et Biophysica Sinica
https://www.readbyqxmd.com/read/28535251/mms1-binds-to-g-rich-regions-in-saccharomyces-cerevisiae-and-influences-replication-and-genome-stability
#4
Katharina Wanzek, Eike Schwindt, John A Capra, Katrin Paeschke
The regulation of replication is essential to preserve genome integrity. Mms1 is part of the E3 ubiquitin ligase complex that is linked to replication fork progression. By identifying Mms1 binding sites genome-wide in Saccharomyces cerevisiae we connected Mms1 function to genome integrity and replication fork progression at particular G-rich motifs. This motif can form G-quadruplex (G4) structures in vitro. G4 are stable DNA structures that are known to impede replication fork progression. In the absence of Mms1, genome stability is at risk at these G-rich/G4 regions as demonstrated by gross chromosomal rearrangement assays...
May 23, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28525650/detection-of-damage-on-single-or-double-stranded-dna-in-a-population-exposed-to-arsenic-in-drinking-water
#5
J Jiménez-Villarreal, D I Rivas-Armendariz, C P Pineda-Belmontes, N D Betancourt-Martínez, M A Macías-Corral, A J Guerra-Alanis, M S Niño-Castañeda, J Morán-Martínez
Different studies have suggested an association between arsenic (As) exposure and damage to single-stranded DNA by reactive oxygen species derived from the biotransformation of arsenic. The single strand damages are converted to double strand damage upon interaction with ultraviolet radiation. Analysis of genomic integrity is important for assessing the genotoxicity caused by environmental pollutants. In this study, we compared the concentration of As in drinking water, nutritional status, lifestyle variables, and the level of genotoxicity in an exposed population and a control group...
May 18, 2017: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/28521287/5azadc-treatment-upregulates-mir-375-level-and-represses-hpv16-e6-expression
#6
Adrien Morel, Aurélie Baguet, Jérôme Perrard, Caroline Demeret, Elise Jacquin, David Guenat, Christiane Mougin, Jean-Luc Prétet
High risk human papillomaviruses are the etiological agents of cervical cancer and HPV16 is the most oncogenic genotype. Immortalization and transformation of infected cells requires the overexpression of the two viral oncoproteins E6 and E7 following HPV DNA integration into the host cell genome. Integration often leads to the loss of the E2 open reading frame and the corresponding protein can no longer act as a transcriptional repressor on p97 promoter. Recently, it has been proposed that long control region methylation also contributes to the regulation of E6/E7 expression...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28512458/a-mitochondrial-autonomously-replicating-sequence-from-pichia-pastoris-for-uniform-high-level-recombinant-protein-production
#7
Jan-Philipp Schwarzhans, Tobias Luttermann, Daniel Wibberg, Anika Winkler, Wolfgang Hübner, Thomas Huser, Jörn Kalinowski, Karl Friehs
Pichia pastoris is a non-conventional methylotrophic yeast that is widely used for recombinant protein production, typically by stably integrating the target gene into the genome as part of an expression cassette. However, the comparatively high clonal variability associated with this approach usually necessitates a time intense screening step in order to find strains with the desired productivity. Some of the factors causing this clonal variability can be overcome using episomal vectors containing an autonomously replicating sequence (ARS)...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28510302/association-study-of-genetic-variation-in-dna-repair-pathway-genes-and-risk-of-basal-cell-carcinoma
#8
Yuan Lin, Harvind S Chahal, Wenting Wu, Hyunje G Cho, Katherine J Ransohoff, Fengju Song, Jean Y Tang, Kavita Y Sarin, Jiali Han
DNA repair plays a critical role in protecting the genome from ultraviolet radiation and maintaining the genomic integrity of cells. Genetic variants in DNA repair-related genes can influence an individual's DNA repair capacity, which may be related to the risk of developing basal cell carcinoma (BCC). We comprehensively assessed the associations of 2,965 independent single-nucleotide polymorphisms (SNPs) across 165 DNA repair pathway genes with BCC risk in a genome-wide association meta-analysis totaling 17,187 BCC cases and 287,054 controls from two data sets...
May 16, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28507144/critical-roles-of-dna-demethylation-in-the-activation-of-ripening-induced-genes-and-inhibition-of-ripening-repressed-genes-in-tomato-fruit
#9
Zhaobo Lang, Yihai Wang, Kai Tang, Dengguo Tang, Tatsiana Datsenka, Jingfei Cheng, Yijing Zhang, Avtar K Handa, Jian-Kang Zhu
DNA methylation is a conserved epigenetic mark important for genome integrity, development, and environmental responses in plants and mammals. Active DNA demethylation in plants is initiated by a family of 5-mC DNA glycosylases/lyases (i.e., DNA demethylases). Recent reports suggested a role of active DNA demethylation in fruit ripening in tomato. In this study, we generated loss-of-function mutant alleles of a tomato gene, SlDML2, which is a close homolog of the Arabidopsis DNA demethylase gene ROS1 In the fruits of the tomato mutants, increased DNA methylation was found in thousands of genes...
May 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28504713/elevated-pttg-and-pbf-predicts-poor-patient-outcome-and-modulates-dna-damage-response-genes-in-thyroid-cancer
#10
M L Read, J C Fong, B Modasia, A Fletcher, W Imruetaicharoenchoke, R J Thompson, H Nieto, J J Reynolds, A Bacon, U Mallick, A Hackshaw, J C Watkinson, K Boelaert, A S Turnell, V E Smith, C J McCabe
The proto-oncogene PTTG and its binding partner PBF have been widely studied in multiple cancer types, particularly thyroid and colorectal, but their combined role in tumourigenesis is uncharacterised. Here, we show for the first time that together PTTG and PBF significantly modulate DNA damage response (DDR) genes, including p53 target genes, required to maintain genomic integrity in thyroid cells. Critically, DDR genes were extensively repressed in primary thyrocytes from a bitransgenic murine model (Bi-Tg) of thyroid-specific PBF and PTTG overexpression...
May 15, 2017: Oncogene
https://www.readbyqxmd.com/read/28491150/dynamic-silencing-of-somatic-l1-retrotransposon-insertions-reflects-the-developmental-and-cellular-contexts-of-their-genomic-integration
#11
Manoj Kannan, Jingfeng Li, Sarah E Fritz, Kathryn E Husarek, Jonathan C Sanford, Teresa L Sullivan, Pawan Kumar Tiwary, Wenfeng An, Jef D Boeke, David E Symer
BACKGROUND: The ongoing mobilization of mammalian transposable elements (TEs) contributes to natural genetic variation. To survey the epigenetic control and expression of reporter genes inserted by L1 retrotransposition in diverse cellular and genomic contexts, we engineered highly sensitive, real-time L1 retrotransposon reporter constructs. RESULTS: Here we describe different patterns of expression and epigenetic controls of newly inserted sequences retrotransposed by L1 in various somatic cells and tissues including cultured human cancer cells, mouse embryonic stem cells, and tissues of pseudofounder transgenic mice and their progeny...
2017: Mobile DNA
https://www.readbyqxmd.com/read/28489851/global-analysis-of-double-strand-break-processing-reveals-in-vivo-properties-of-the-helicase-nuclease-complex-addab
#12
Anjana Badrinarayanan, Tung B K Le, Jan-Hendrik Spille, Ibrahim I Cisse, Michael T Laub
In bacteria, double-strand break (DSB) repair via homologous recombination is thought to be initiated through the bi-directional degradation and resection of DNA ends by a helicase-nuclease complex such as AddAB. The activity of AddAB has been well-studied in vitro, with translocation speeds between 400-2000 bp/s on linear DNA suggesting that a large section of DNA around a break site is processed for repair. However, the translocation rate and activity of AddAB in vivo is not known, and how AddAB is regulated to prevent excessive DNA degradation around a break site is unclear...
May 10, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28485371/differences-between-germline-and-somatic-mutation-rates-in-humans-and-mice
#13
Brandon Milholland, Xiao Dong, Lei Zhang, Xiaoxiao Hao, Yousin Suh, Jan Vijg
The germline mutation rate has been extensively studied and has been found to vary greatly between species, but much less is known about the somatic mutation rate in multicellular organisms, which remains very difficult to determine. Here, we present data on somatic mutation rates in mice and humans, obtained by sequencing single cells and clones derived from primary fibroblasts, which allows us to make the first direct comparison with germline mutation rates in these two species. The results indicate that the somatic mutation rate is almost two orders of magnitude higher than the germline mutation rate and that both mutation rates are significantly higher in mice than in humans...
May 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28483799/female-to-male-sex-reversal-associated-with-unique-xp21-2-deletion-disrupting-genomic-regulatory-architecture-of-the-dosage-sensitive-sex-reversal-region
#14
Pankaj Dangle, María Sol Touzon, Miguel Reyes-Múgica, Selma F Witchel, Aleksandar Rajkovic, Francis X Schneck, Svetlana A Yatsenko
BACKGROUND: The XX male disorder of sex development (DSD) is a rare condition that is most commonly associated with the presence of the SRY gene on one of the X chromosomes due to unequal crossing-over between sex chromosomes during spermatogenesis. However, in about 20% of the XX male individuals, SRY is missing, although these persons have at least some testis differentiation. The genetic basis of genital ambiguity and the mechanisms triggering testis development in such patients remain unknown...
May 8, 2017: Journal of Medical Genetics
https://www.readbyqxmd.com/read/28482095/prl-3-promotes-telomere-deprotection-and-chromosomal-instability
#15
Shenyi Lian, Lin Meng, Yongyong Yang, Ting Ma, Xiaofang Xing, Qin Feng, Qian Song, Caiyun Liu, Zhihua Tian, Like Qu, Chengchao Shou
Phosphatase of regenerating liver (PRL-3) promotes cell invasiveness, but its role in genomic integrity remains unknown. We report here that shelterin component RAP1 mediates association between PRL-3 and TRF2. In addition, TRF2 and RAP1 assist recruitment of PRL-3 to telomeric DNA. Silencing of PRL-3 in colon cancer cells does not affect telomere integrity or chromosomal stability, but induces reactive oxygen species-dependent DNA damage response and senescence. However, overexpression of PRL-3 in colon cancer cells and primary fibroblasts promotes structural abnormalities of telomeres, telomere deprotection, DNA damage response, chromosomal instability and senescence...
May 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28481984/the-dna-damage-response-ddr-is-induced-by-the-c9orf72-repeat-expansion-in-amyotrophic-lateral-sclerosis
#16
Manal A Farg, Anna Konopka, Kai Ying Soo, Daisuke Ito, Julie D Atkin
Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease affecting motor neurons. Hexanucleotide (GGGGCC) repeat expansions in a non-coding region of C9orf72 are the major cause of familial ALS and frontotemporal dementia (FTD) worldwide. The C9orf72 repeat expansion undergoes repeat-associated non-ATG (RAN) translation to produce five dipeptide repeat proteins (DRPs), including poly(GR) and poly(PR). Whilst it remains unclear how mutations in C9orf72 lead to neurodegeneration in ALS/FTD, dysfunction to the nucleolus and R loop formation are implicated as pathogenic mechanisms...
May 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28481879/cytoplasmic-e3-ubiquitin-ligase-cul9-controls-cell-proliferation-senescence-apoptosis-and-genome-integrity-through-p53
#17
Z Li, Y Xiong
CUL9 is a member of the cullin family of E3 ubiquitin ligases, and it localizes predominantly in the cytoplasm. Deletion of Cul9 in mice results in increased DNA damage, widespread aneuploidy, spontaneous tumor development, accelerated Eμ-Myc-induced lymphomagenesis and susceptibility to carcinogenesis. CUL9 binds to p53 and causes cell apoptosis when ectopically expressed. Whether the function of CUL9 in maintaining genomic integrity and suppressing tumorigenesis is linked to p53 has not been genetically tested...
May 8, 2017: Oncogene
https://www.readbyqxmd.com/read/28477133/dna-damage-response-in-human-stem-cells-and-neural-descendants
#18
Jason M Beckta, Bret R Adams, Kristoffer Valerie
Glial cells are crucial for the normal function of neurons and are intricately involved in the pathogenesis of neurodegenerative diseases as well as neurologic malignancies. A deeper understanding of the mechanisms by which glial cells influence the development of such pathologies will undoubtedly lead to new and improved therapeutic approaches. Commercially available human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), both of which can be differentiated into neural progenitors (NPs) and various neural cell lineages, have become widely used as sources for producing normal human central nervous system (CNS) cells...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28477131/noncanonical-atm-activation-and-signaling-in-response-to-transcription-blocking-dna-damage
#19
Jurgen A Marteijn, Wim Vermeulen, Maria Tresini
Environmental genotoxins and metabolic byproducts generate DNA lesions that can cause genomic instability and disrupt tissue homeostasis. To ensure genomic integrity, cells employ mechanisms that convert signals generated by stochastic DNA damage into organized responses, including activation of repair systems, cell cycle checkpoints, and apoptotic mechanisms. DNA damage response (DDR) signaling pathways coordinate these responses and determine cellular fates in part, by transducing signals that modulate RNA metabolism...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28477130/monitoring-dna-repair-consequences-of-atm-signaling-using-simultaneous-fluorescent-readouts
#20
Adrian Wiegmans
The repair of deleterious DNA double strand breaks is required to maintain genome integrity. The efficacy in which this occurs relies upon the available machinery and is guided by factors that include cell cycle status, availability of donor template, and the local chromosome structure. Therefore at a single DNA breakpoint there are different outcomes that can occur. The Traffic light reporter (TLR) assay protocol is a dual fluorescent readout that has the ability to monitor simultaneous homologous recombination and non-homologous end joining activity in response to DNA damage...
2017: Methods in Molecular Biology
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