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https://www.readbyqxmd.com/read/27926867/genomic-instability-is-induced-by-persistent-proliferation-of-cells-undergoing-epithelial-to-mesenchymal-transition
#1
Valentine Comaills, Lilian Kabeche, Robert Morris, Rémi Buisson, Min Yu, Marissa Wells Madden, Joseph A LiCausi, Myriam Boukhali, Ken Tajima, Shiwei Pan, Nicola Aceto, Srinjoy Sil, Yu Zheng, Tilak Sundaresan, Toshifumi Yae, Nicole Vincent Jordan, David T Miyamoto, David T Ting, Sridhar Ramaswamy, Wilhelm Haas, Lee Zou, Daniel A Haber, Shyamala Maheswaran
TGF-β secreted by tumor stroma induces epithelial-to-mesenchymal transition (EMT) in cancer cells, a reversible phenotype linked to cancer progression and drug resistance. However, exposure to stromal signals may also lead to heritable changes in cancer cells, which are poorly understood. We show that epithelial cells failing to undergo proliferation arrest during TGF-β-induced EMT sustain mitotic abnormalities due to failed cytokinesis, resulting in aneuploidy. This genomic instability is associated with the suppression of multiple nuclear envelope proteins implicated in mitotic regulation and is phenocopied by modulating the expression of LaminB1...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27924006/the-homologous-recombination-protein-rad51d-protects-the-genome-from-large-deletions
#2
Wade A Reh, Rodney S Nairn, Megan P Lowery, Karen M Vasquez
Homologous recombination (HR) is a DNA double-strand break (DSB) repair pathway that protects the genome from chromosomal instability. RAD51 mediator proteins (i.e. paralogs) are critical for efficient HR in mammalian cells. However, how HR-deficient cells process DSBs is not clear. Here, we utilized a loss-of-function HR-reporter substrate to simultaneously monitor HR-mediated gene conversion and non-conservative mutation events. The assay is designed around a heteroallelic duplication of the Aprt gene at its endogenous locus in isogenic Chinese hamster ovary cell lines...
December 6, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27923837/the-nci-60-methylome-and-its-integration-into-cellminer
#3
William C Reinhold, Sudhir Varma, Margot Sunshine, Vinodh Rajapakse, Augustin Luna, Kurt W Kohn, Holly Stevenson, Yonghong Wang, Holger Heyn, Vanesa Nogales, Sebastian Moran, David J Goldstein, James H Doroshow, Paul S Meltzer, Manel Esteller, Yves Pommier
A unique resource for systems pharmacology and genomic studies is the NCI-60 cancer cell line panel, which provides data for the largest publicly available library of compounds with cytotoxic activity (~21,000 compounds), including 108 FDA-approved and 70 clinical trial drugs as well as genomic data, including whole-exome sequencing, gene and microRNA transcripts, DNA copy number, and protein levels. Here we provide the first readily usable genome-wide DNA methylation database for the NCI-60, including 485,577 probes from the Infinium HumanMethylation450k BeadChip array, which yielded DNA methylation signatures for 17,559 genes integrated into our open access CellMiner version 2...
December 6, 2016: Cancer Research
https://www.readbyqxmd.com/read/27923713/when-transcription-goes-on-holliday-double-holliday-junctions-block-rna-polymerase-ii-transcription-in-vitro
#4
Anne Pipathsouk, Boris P Belotserkovskii, Philip C Hanawalt
Non-canonical DNA structures can obstruct transcription. This transcription blockage could have various biological consequences, including genomic instability and gratuitous transcription-coupled repair. Among potential structures causing transcription blockage are Holliday junctions (HJ), which can be generated as intermediates in homologous recombination or during processing of stalled replication forks. Of particular interest is the double Holliday junction (DHJ), which contains two HJs. Topological considerations impose the constraint that the total number of helical turns in the DNA duplexes between the junctions cannot be altered as long as the flanking DNA duplexes are intact...
December 3, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27922175/a-framework-to-quantify-karyotype-variation-associated-with-cho-production-instability
#5
Jong Youn Baik, Kelvin H Lee
Chinese hamster ovary (CHO) cells, major mammalian host cells for biomanufacturing of therapeutic proteins, have been extensively investigated to enhance productivity and product quality. However, cell line instability resulting in unexpected changes in productivity or product quality is challenging for biomanufacturing. Based on previous reports about causes and characteristics of production instability, we hypothesized that chromosomal rearrangements due to genomic instability are associated with production instability...
December 6, 2016: Biotechnology and Bioengineering
https://www.readbyqxmd.com/read/27922005/wrn-regulates-pathway-choice-between-classical-and-alternative-non-homologous-end-joining
#6
Raghavendra A Shamanna, Huiming Lu, Jessica K de Freitas, Jane Tian, Deborah L Croteau, Vilhelm A Bohr
Werner syndrome (WS) is an accelerated ageing disorder with genomic instability caused by WRN protein deficiency. Many features seen in WS can be explained by the diverse functions of WRN in DNA metabolism. However, the origin of the large genomic deletions and telomere fusions are not yet understood. Here, we report that WRN regulates the pathway choice between classical (c)- and alternative (alt)-nonhomologous end joining (NHEJ) during DNA double-strand break (DSB) repair. It promotes c-NHEJ via helicase and exonuclease activities and inhibits alt-NHEJ using non-enzymatic functions...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27921283/choices-have-consequences-the-nexus-between-dna-repair-pathways-and-genomic-instability-in-cancer
#7
REVIEW
Sonali Bhattacharjee, Saikat Nandi
BACKGROUND: The genome is under constant assault from a multitude of sources that can lead to the formation of DNA double-stand breaks (DSBs). DSBs are cytotoxic lesions, which if left unrepaired could lead to genomic instability, cancer and even cell death. However, erroneous repair of DSBs can lead to chromosomal rearrangements and loss of heterozygosity, which in turn can also cause cancer and cell death. Hence, although the repair of DSBs is crucial for the maintenance of genome integrity the process of repair need to be well regulated and closely monitored...
December 2016: Clinical and Translational Medicine
https://www.readbyqxmd.com/read/27919340/consequences-of-irradiation-on-adult-spermatogenesis-between-infertility-and-hereditary-risk
#8
Henri-Baptiste Marjault, Isabelle Allemand
DNA damage response in adult spermatogenic cells should limit the propagation of mutations to the offspring, without being detrimental to fertility. In differentiating spermatogenic cells, the genomic instability is limited in time, whereas in spermatogonial stem cells it can be maintained all along life. Spermatogonial stem cells are long-lived cells that support normal germ cell differentiation and must be preserved throughout life. However after irradiation spermatogenesis recovery can be impaired as a consequence of the radiation-induced decline in spermatogonial stem cell...
October 2016: Mutation Research
https://www.readbyqxmd.com/read/27918550/selective-y-centromere-inactivation-triggers-chromosome-shattering-in-micronuclei-and-repair-by-non-homologous-end-joining
#9
Peter Ly, Levi S Teitz, Dong H Kim, Ofer Shoshani, Helen Skaletsky, Daniele Fachinetti, David C Page, Don W Cleveland
Chromosome missegregation into a micronucleus can cause complex and localized genomic rearrangements known as chromothripsis, but the underlying mechanisms remain unresolved. Here we developed an inducible Y centromere-selective inactivation strategy by exploiting a CENP-A/histone H3 chimaera to directly examine the fate of missegregated chromosomes in otherwise diploid human cells. Using this approach, we identified a temporal cascade of events that are initiated following centromere inactivation involving chromosome missegregation, fragmentation, and re-ligation that span three consecutive cell cycles...
December 5, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27917697/current-and-future-biomarkers-in-the-treatment-of-colorectal-cancer
#10
Pieter-Jan Cuyle, Hans Prenen
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. CRC develops as a consequence of genomic instability, characterized by various genetic and epigenetic alterations. Its molecular heterogeneity explains the large variability in patient prognosis and treatment response, emphasizing the need for development of accurate prognostic and predictive biomarkers. This article delineates the different pathways of colorectal carcinogenesis and its molecular subtype classification. With this review, we aim to provide a comprehensive overview of the current and future biomarkers guiding clinical decision-making and CRC treatment...
December 5, 2016: Acta Clinica Belgica
https://www.readbyqxmd.com/read/27916875/proteinase-activated-receptor-2-is-a-novel-regulator-of-tgf-%C3%AE-signaling-in-pancreatic-cancer
#11
REVIEW
David Witte, Franziska Zeeh, Thomas Gädeken, Frank Gieseler, Bernhard H Rauch, Utz Settmacher, Roland Kaufmann, Hendrik Lehnert, Hendrik Ungefroren
TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous mechanisms and genetic alterations such as genomic instability and somatic mutations, but also by a plethora of external signals derived from the tumor microenvironment, such as cell-to-cell interactions, growth factors and extracellular matrix proteins and proteolytic enzymes...
November 30, 2016: Journal of Clinical Medicine
https://www.readbyqxmd.com/read/27916001/sirtuins-in-metabolism-dna-repair-and-cancer
#12
REVIEW
Zhen Mei, Xian Zhang, Jiarong Yi, Junjie Huang, Jian He, Yongguang Tao
The mammalian sirtuin family has attracted tremendous attention over the past few years as stress adaptors and post-translational modifier. They have involved in diverse cellular processes including DNA repair, energy metabolism, and tumorigenesis. Notably, genomic instability and metabolic reprogramming are two of characteristic hallmarks in cancer. In this review, we summarize current knowledge on the functions of sirtuins mainly regarding DNA repair and energy metabolism, and further discuss the implication of sirtuins in cancer specifically by regulating genome integrity and cancer-related metabolism...
December 5, 2016: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/27914716/replication-stalling-and-dna-microsatellite-instability
#13
M Leffak, R Gadgil, J Barthelemy, T Lewis
Microsatellites are short, tandemly repeated DNA motifs of 1-6 nucleotides, also termed simple sequence repeats (SRSs) or short tandem repeats (STRs). Collectively, these repeats comprise approximately 3% of the human genome Subramanian et al. (2003), Lander and Lander (2001) [1,2], and represent a large reservoir of loci highly prone to mutations Sun et al. (2012), Ellegren (2004) [3,4] that contribute to human evolution and disease. Microsatellites are known to stall and reverse replication forks in model systems Pelletier et al...
November 22, 2016: Biophysical Chemistry
https://www.readbyqxmd.com/read/27913357/introducing-a-stable-bootstrap-validation-framework-for-reliable-genomic-signature-extraction
#14
Nikolaos-Kosmas Chlis, Ekaterini S Bei, Michael Zervakis
The application of machine learning methods for the identification of candidate genes responsible for phenotypes of interest, such as cancer, is a major challenge in the field of bioinformatics. These lists of genes are often called genomic signatures and their linkage to phenotype associations may form a significant step in discovering the causation between genotypes and phenotypes. Traditional methods that produce genomic signatures from DNA Microarray data tend to extract significantly different lists under relatively small variations of the training data...
November 29, 2016: IEEE/ACM Transactions on Computational Biology and Bioinformatics
https://www.readbyqxmd.com/read/27911848/global-analysis-of-genomic-instability-caused-by-dna-replication-stress-in-saccharomyces-cerevisiae
#15
Dao-Qiong Zheng, Ke Zhang, Xue-Chang Wu, Piotr A Mieczkowski, Thomas D Petes
DNA replication stress (DRS)-induced genomic instability is an important factor driving cancer development. To understand the mechanisms of DRS-associated genomic instability, we measured the rates of genomic alterations throughout the genome in a yeast strain with lowered expression of the replicative DNA polymerase δ. By a genetic test, we showed that most recombinogenic DNA lesions were introduced during S or G2 phase, presumably as a consequence of broken replication forks. We observed a high rate of chromosome loss, likely reflecting a reduced capacity of the low-polymerase strains to repair double-stranded DNA breaks (DSBs)...
November 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27910065/pathology-of-endometrial-carcinoma
#16
Sigurd F Lax
On a clinicopathological and molecular level, two distinctive types of endometrial carcinoma, type I and type II, can be distinguished. Endometrioid carcinoma, the typical type I carcinoma, seems to develop through an estrogen-driven "adenoma carcinoma" pathway from atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN). It is associated with elevated serum estrogen and high body mass index and expresses estrogen and progesterone receptors. They are mostly low grade and show a favorable prognosis...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/27908669/cellular-responses-to-replication-stress-implications-in-cancer-biology-and-therapy
#17
REVIEW
Hui-Ju Hsieh, Guang Peng
DNA replication is essential for cell proliferation. Any obstacles during replication cause replication stress, which may lead to genomic instability and cancer formation. In this review, we summarize the physiological DNA replication process and the normal cellular response to replication stress. We also outline specialized therapies in clinical trials based on current knowledge and future perspectives in the field.
November 22, 2016: DNA Repair
https://www.readbyqxmd.com/read/27908614/a-critical-discussion-on-diet-genomic-mutations-and-repair-mechanisms-in-colon-carcinogenesis
#18
Juliana Yumi Sakita, Bianca Gasparotto, Sergio Britto Garcia, Sergio Akira Uyemura, Vinicius Kannen
Colon cancer is one of the most common malignancies and its etiology closely tied to dietary habits. Recent epidemiological data shows that colon cancer incidence is shifting to a much younger population. In this regard, some dietary components from a regular human meal might have various DNA-damaging compounds. Given that not every person endure cancer, the colonic malignancy develops throughout decades, and persistent DNA damage promotes cancer when induced at the proper intensity, a critical discussion of possible novel mechanisms by which carcinogens promote these tumors is urgently needed...
November 28, 2016: Toxicology Letters
https://www.readbyqxmd.com/read/27908234/sustained-early-disruption-of-mitochondrial-function-contributes-to-arsenic-induced-prostate-tumorigenesis
#19
B Singh, M Kulawiec, K M Owens, A Singh, K K Singh
Arsenic is a well-known human carcinogen that affects millions of people worldwide, but the underlying mechanisms of carcinogenesis are unclear. Several epidemiological studies have suggested increased prostate cancer incidence and mortality due to exposure to arsenic. Due to lack of an animal model of arsenic-induced carcinogenesis, we used a prostate epithelial cell culture model to identify a role for mitochondria in arsenic-induced prostate cancer. Mitochondrial morphology and membrane potential was impacted within a few hours of arsenic exposure of non-neoplastic prostate epithelial cells...
October 2016: Biochemistry. Biokhimii︠a︡
https://www.readbyqxmd.com/read/27907175/p53-specifically-binds-triplex-dna-in-vitro-and-in-cells
#20
Marie Brázdová, Vlastimil Tichý, Robert Helma, Pavla Bažantová, Alena Polášková, Aneta Krejčí, Marek Petr, Lucie Navrátilová, Olga Tichá, Karel Nejedlý, Martin L Bennink, Vinod Subramaniam, Zuzana Bábková, Tomáš Martínek, Matej Lexa, Matej Adámik
Triplex DNA is implicated in a wide range of biological activities, including regulation of gene expression and genomic instability leading to cancer. The tumor suppressor p53 is a central regulator of cell fate in response to different type of insults. Sequence and structure specific modes of DNA recognition are core attributes of the p53 protein. The focus of this work is the structure-specific binding of p53 to DNA containing triplex-forming sequences in vitro and in cells and the effect on p53-driven transcription...
2016: PloS One
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