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https://www.readbyqxmd.com/read/28645654/epigenome-dysregulation-in-cholangiocarcinoma
#1
REVIEW
Colm J O'Rourke, Patricia Munoz-Garrido, Esmeralda L Aguayo, Jesper B Andersen
Epigenomics is a fast-evolving field of research that has lately attracted considerable interest, mainly due to the reversibility of epigenetic marks. Clinically, among solid tumors, the field is still limited. In cholangiocarcinoma (CCA) it is well known that the epigenetic landscape is deregulated both during carcinogenesis and disease progression as a consequence of aberrant mechanisms leading to genome instability. In this article, we will briefly review the molecular alterations that have been described in the transformation of normal cholangiocytes into malignant derivatives, focusing on the role of non-coding RNA (ncRNA) interactions, DNA methylation, post-translational modifications (PTMs) of histones and chromatin remodeling complexes...
June 20, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28645372/analysis-of-structure-selective-endonuclease-activities-from-yeast-and-human-extracts
#2
Joao Matos, Stephen C West
The efficient separation of two equal DNA masses to the daughter cells is an essential step in mitosis. This process is dependent upon the removal of any remaining recombination or replication intermediates that link sister chromatids, and a failure to resolve these intermediates leads to genome instability. Similarly, a failure to resolve meiotic recombination intermediates that link homologous chromosomes can cause chromosome nondisjunction and aneuploidy. Cleavage of these potentially toxic replication/recombination intermediates requires the Mus81 endonuclease, which is active upon flaps, forks, and more complex secondary structures in DNA such as Holliday junctions...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28645367/base-excision-repair-variants-in-cancer
#3
Carolyn G Marsden, Julie A Dragon, Susan S Wallace, Joann B Sweasy
Base excision repair (BER) is a key genome maintenance pathway that removes endogenously damaged DNA bases that arise in cells at very high levels on a daily basis. Failure to remove these damaged DNA bases leads to increased levels of mutagenesis and chromosomal instability, which have the potential to drive carcinogenesis. Next-generation sequencing of the germline and tumor genomes of thousands of individuals has uncovered many rare mutations in BER genes. Given that BER is critical for genome maintenance, it is important to determine whether BER genomic variants have functional phenotypes...
2017: Methods in Enzymology
https://www.readbyqxmd.com/read/28642863/friends-enemies-endogenous-retroviruses-are-major-transcriptional-regulators-of-human-dna
#4
REVIEW
Anton A Buzdin, Vladimir Prassolov, Andrew V Garazha
Endogenous retroviruses are mobile genetic elements hardly distinguishable from infectious, or "exogenous," retroviruses at the time of insertion in the host DNA. Human endogenous retroviruses (HERVs) are not rare. They gave rise to multiple families of closely related mobile elements that occupy ~8% of the human genome. Together, they shape genomic regulatory landscape by providing at least ~320,000 human transcription factor binding sites (TFBS) located on ~110,000 individual HERV elements. The HERVs host as many as 155,000 mapped DNaseI hypersensitivity sites, which denote loci active in the regulation of gene expression or chromatin structure...
2017: Frontiers in Chemistry
https://www.readbyqxmd.com/read/28641942/the-top1-paradox-friend-and-foe-of-the-eukaryotic-genome
#5
REVIEW
Nayun Kim, Sue Jinks-Robertson
Topoisomerases manage the torsional stress associated with the separation of DNA strands during transcription and DNA replication. Eukaryotic Topoisomerase I (Top1) is a Type IB enzyme that nicks and rejoins only one strand of duplex DNA, and it is especially important during transcription. By resolving transcription-associated torsional stress, Top1 reduces the accumulation of genome-destabilizing R-loops and non-B DNA structures. The DNA nicking activity of Top1, however, can also initiate genome instability in the form of illegitimate recombination, homologous recombination and mutagenesis...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28641941/role-of-recombination-and-replication-fork-restart-in-repeat-instability
#6
REVIEW
Erica J Polleys, Nealia C M House, Catherine H Freudenreich
Eukaryotic genomes contain many repetitive DNA sequences that exhibit size instability. Some repeat elements have the added complication of being able to form secondary structures, such as hairpin loops, slipped DNA, triplex DNA or G-quadruplexes. Especially when repeat sequences are long, these DNA structures can form a significant impediment to DNA replication and repair, leading to DNA nicks, gaps, and breaks. In turn, repair or replication fork restart attempts within the repeat DNA can lead to addition or removal of repeat elements, which can sometimes lead to disease...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28641940/dormant-origins-as-a-built-in-safeguard-in-eukaryotic-dna-replication-against-genome-instability-and-disease-development
#7
REVIEW
Naoko Shima, Kayla D Pederson
DNA replication is a prerequisite for cell proliferation, yet it can be increasingly challenging for a eukaryotic cell to faithfully duplicate its genome as its size and complexity expands. Dormant origins now emerge as a key component for cells to successfully accomplish such a demanding but essential task. In this perspective, we will first provide an overview of the fundamental processes eukaryotic cells have developed to regulate origin licensing and firing. With a special focus on mammalian systems, we will then highlight the role of dormant origins in preventing replication-associated genome instability and their functional interplay with proteins involved in the DNA damage repair response for tumor suppression...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28641873/targeting-dna-repair-for-precision-radiotherapy-balancing-the-therapeutic-ratio
#8
REVIEW
Osman Mahamud, Jonathan So, Melvin L K Chua, Robert G Bristow
Genomic instability is underpinned by defects in the DNA damage response and DNA repair pathways. Subsequent clonal selection and adaption can lead to a mutator phenotype and tumor aggression. Importantly, tumor cell sensitivity to chemotherapy and radiotherapy can depend highly on the cellular capacity to repair DNA damage within and between tumor types. Annotation of functional defects in DNA damage response and DNA repair function may allow for the development of novel prognostic biomarkers. This information could also be used to predict therapeutic response, including predicting responses following inhibition of DNA repair...
April 25, 2017: Current Problems in Cancer
https://www.readbyqxmd.com/read/28638452/targeting-tpx2-suppresses-the-tumorigenesis-of-hepatocellular-carcinoma-cells-resulting-in-arrested-mitotic-phase-progression-and-increased-genomic-instability
#9
Chao-Wen Hsu, Yu-Chia Chen, Hsing-Hao Su, Guan-Jin Huang, Chih-Wen Shu, Tony Tong-Lin Wu, Hung-Wei Pan
Hepatocellular carcinoma (HCC) remains one of the most difficult cancers to treat, with chemotherapies being relatively ineffective. Therefore, a better knowledge of molecular hepatocarcinogenesis will provide opportunities for designing targeted therapies. TPX2 (targeting protein for Xklp2) is overexpressed as a consequence of oncogenic alterations and is likely to alter the proper regulation of chromosome segregation in cancer cells. Disrupting the machinery which is responsible for mitosis and chromosome instability in cancer cells can be one of the most successful strategies for cancer therapy...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/28637190/evolution-of-the-sperm-methylome-of-primates-is-associated-with-retrotransposon-insertions-and-genome-instability
#10
Kei Fukuda, Yukihiro Inoguchi, Kenji Ichiyanagi, Tomoko Ichiyanagi, Yasuhiro Go, Masashi Nagano, Yojiro Yanagawa, Noboru Takaesu, Yasuyuki Ohkawa, Hiroo Imai, Hiroyuki Sasaki
Changes in gene expression resulting from epigenetic and/or genetic changes play an important role in the evolutionary divergence of phenotypes. To explore how epigenetic and genetic changes are linked during primate evolution, we have compared the genome-wide DNA methylation profiles (methylomes) of humans and chimpanzees, which have a 1.2% DNA sequence divergence, of sperm, the frontal cortices, B cells, and neutrophils. We revealed that species-specific differentially methylated regions (S-DMRs), ranging from several hundred bp to several kb, were frequently associated with sequence changes in transcription factor binding sites and insertions of Alu and SVA retrotransposons...
June 20, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28633018/chromosome-mis-segregation-generates-cell-cycle-arrested-cells-with-complex-karyotypes-that-are-eliminated-by-the-immune-system
#11
Stefano Santaguida, Amelia Richardson, Divya Ramalingam Iyer, Ons M'Saad, Lauren Zasadil, Kristin A Knouse, Yao Liang Wong, Nicholas Rhind, Arshad Desai, Angelika Amon
Aneuploidy, a state of karyotype imbalance, is a hallmark of cancer. Changes in chromosome copy number have been proposed to drive disease by modulating the dosage of cancer driver genes and by promoting cancer genome evolution. Given the potential of cells with abnormal karyotypes to become cancerous, do pathways that limit the prevalence of such cells exist? By investigating the immediate consequences of aneuploidy on cell physiology, we identified mechanisms that eliminate aneuploid cells. We find that chromosome mis-segregation leads to further genomic instability that ultimately causes cell-cycle arrest...
June 19, 2017: Developmental Cell
https://www.readbyqxmd.com/read/28632202/genome-wide-association-study-of-borderline-personality-disorder-reveals-genetic-overlap-with-bipolar-disorder-major-depression-and-schizophrenia
#12
S H Witt, F Streit, M Jungkunz, J Frank, S Awasthi, C S Reinbold, J Treutlein, F Degenhardt, A J Forstner, S Heilmann-Heimbach, L Dietl, C E Schwarze, D Schendel, J Strohmaier, A Abdellaoui, R Adolfsson, T M Air, H Akil, M Alda, N Alliey-Rodriguez, O A Andreassen, G Babadjanova, N J Bass, M Bauer, B T Baune, F Bellivier, S Bergen, A Bethell, J M Biernacka, D H R Blackwood, M P Boks, D I Boomsma, A D Børglum, M Borrmann-Hassenbach, P Brennan, M Budde, H N Buttenschøn, E M Byrne, P Cervantes, T-K Clarke, N Craddock, C Cruceanu, D Curtis, P M Czerski, U Dannlowski, T Davis, E J C de Geus, A Di Florio, S Djurovic, E Domenici, H J Edenberg, B Etain, S B Fischer, L Forty, C Fraser, M A Frye, J M Fullerton, K Gade, E S Gershon, I Giegling, S D Gordon, K Gordon-Smith, H J Grabe, E K Green, T A Greenwood, M Grigoroiu-Serbanescu, J Guzman-Parra, L S Hall, M Hamshere, J Hauser, M Hautzinger, U Heilbronner, S Herms, S Hitturlingappa, P Hoffmann, P Holmans, J-J Hottenga, S Jamain, I Jones, L A Jones, A Juréus, R S Kahn, J Kammerer-Ciernioch, G Kirov, S Kittel-Schneider, S Kloiber, S V Knott, M Kogevinas, M Landén, M Leber, M Leboyer, Q S Li, J Lissowska, S Lucae, N G Martin, F Mayoral-Cleries, S L McElroy, A M McIntosh, J D McKay, A McQuillin, S E Medland, C M Middeldorp, Y Milaneschi, P B Mitchell, G W Montgomery, G Morken, O Mors, T W Mühleisen, B Müller-Myhsok, R M Myers, C M Nievergelt, J I Nurnberger, M C O'Donovan, L M O Loohuis, R Ophoff, L Oruc, M J Owen, S A Paciga, B W J H Penninx, A Perry, A Pfennig, J B Potash, M Preisig, A Reif, F Rivas, G A Rouleau, P R Schofield, T G Schulze, M Schwarz, L Scott, G C B Sinnamon, E A Stahl, J Strauss, G Turecki, S Van der Auwera, H Vedder, J B Vincent, G Willemsen, C C Witt, N R Wray, H S Xi, A Tadic, N Dahmen, B H Schott, S Cichon, M M Nöthen, S Ripke, A Mobascher, D Rujescu, K Lieb, S Roepke, C Schmahl, M Bohus, M Rietschel
Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP...
June 20, 2017: Translational Psychiatry
https://www.readbyqxmd.com/read/28631340/insights-into-the-genomic-plasticity-of-pseudomonas-putida-kf715-a-strain-with-unique-biphenyl-utilizing-activity-and-genome-instability-properties
#13
Hikaru Suenaga, Hidehiko Fujihara, Nobutada Kimura, Jun Hirose, Takahito Watanabe, Taiki Futagami, Masatoshi Goto, Jun Shimodaira, Kensuke Furukawa
Pseudomonas putida KF715 exhibits unique properties in both catabolic activity and genome plasticity. Our previous studies revealed that the DNA region containing biphenyl and salycilate metabolism gene clusters (termed the bph-sal element) was frequently deleted and transferred by conjugation to closely related P. putida strains. In this study, we first determined the complete nucleotide sequence of the KF715 genome. Next, to determine the underlying cause of genome plasticity in KF715, we compared the KF715 genome with the genomes of one KF715 defective mutant, two transconjugants, and several P...
June 19, 2017: Environmental Microbiology Reports
https://www.readbyqxmd.com/read/28630313/targeting-reactive-nitrogen-species-suppresses-hereditary-pancreatic-cancer
#14
Mo Li, Qian Chen, Teng Ma, Xiaochun Yu
Germline mutation of BRCA2 induces hereditary pancreatic cancer. However, how BRCA2 mutation specifically induces pancreatic tumorigenesis remains elusive. Here, we have examined a mouse model of Brca2-deficiency-induced pancreatic tumors and found that excessive reactive nitrogen species (RNS), such as nitrite, are generated in precancerous pancreases, which induce massive DNA damage, including DNA double-strand breaks. RNS-induced DNA lesions cause genomic instability in the absence of Brca2. Moreover, with the treatment of antioxidant tempol to suppress RNS, not only are DNA lesions significantly reduced, but also the onset of pancreatic cancer is delayed...
June 19, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28630051/dna-damage-and-repair-biomarkers-of-immunotherapy-response
#15
REVIEW
Kent W Mouw, Michael S Goldberg, Panagiotis A Konstantinopoulos, Alan D D'Andrea
DNA-damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the antitumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies...
June 19, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28629777/mechanistic-insights-into-transcription-coupled-dna-repair
#16
REVIEW
Bibhusita Pani, Evgeny Nudler
Transcription-coupled DNA repair (TCR) acts on lesions in the transcribed strand of active genes. Helix distorting adducts and other forms of DNA damage often interfere with the progression of the transcription apparatus. Prolonged stalling of RNA polymerase can promote genome instability and also induce cell cycle arrest and apoptosis. These generally unfavorable events are counteracted by RNA polymerase-mediated recruitment of specific proteins to the sites of DNA damage to perform TCR and eventually restore transcription...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28629776/unveiling-the-non-repair-face-of-the-base-excision-repair-pathway-in-rna-processing-a-missing-link-between-dna-repair-and-gene-expression
#17
REVIEW
Giulia Antoniali, Matilde Clarissa Malfatti, Gianluca Tell
The Base Excision Repair (BER) pathway, initially studied as a mere DNA repair pathway, has been later found to be implicated in the expression of cancer related genes in human. For several years, this intricate involvement in apparently different processes represented a mystery, which we now are starting to unveil. The BER handles simple alkylation and oxidative lesions arising from both endogenous and exogenous sources, including cancer therapy agents. Surprisingly, BER pathway involvement in transcriptional regulation, immunoglobulin variability and switch recombination, RNA metabolism and nucleolar function is astonishingly consolidating...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28629774/genome-instabilities-arising-from-ribonucleotides-in-dna
#18
REVIEW
Hannah L Klein
Genomic DNA is transiently contaminated with ribonucleotide residues during the process of DNA replication through misincorporation by the replicative DNA polymerases α, δ and ε, and by the normal replication process on the lagging strand, which uses RNA primers. These ribonucleotides are efficiently removed during replication by RNase H enzymes and the lagging strand synthesis machinery. However, when ribonucleotides remain in DNA they can distort the DNA helix, affect machineries for DNA replication, transcription and repair, and can stimulate genomic instabilities which are manifest as increased mutation, recombination and chromosome alterations...
June 9, 2017: DNA Repair
https://www.readbyqxmd.com/read/28629288/p53-mutation-and-epigenetic-imprinted-igf2-h19-gene-analysis-in-mesenchymal-stem-cells-derived-from-amniotic-fluid-amnion-endometrium-and-wharton-s-jelly
#19
Tatsanee Phermthai, Puttachart Pokathikorn, Suparat Wichitwiengrat, Sasiprapa Thongbopit, Kittima Tungprasertpol, Suphakde Julavijitphong
Mesenchymal stem cells (MSC) are promising cells for medical therapy. In in vitro expansion, MSC can give rise to progeny with genomic and epigenomic alterations, resulting in senescence, loss terminal differentiation and transformation to cancer. However, MSC genome protects its genetic instability via a guardian function of the P53 tumor suppressor gene and epigenetic balance system during MSC culture. Mutations of P53 and epigenetic alterations have been reported to disrupt the quality and quantity of MSC and initiate tumorigenesis...
June 19, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28628113/microrna-20a-mediated-loss-of-autophagy-contributes-to-breast-tumorigenesis-by-promoting-genomic-damage-and-instability
#20
L Liu, J He, X Wei, G Wan, Y Lao, W Xu, Z Li, H Hu, Z Hu, X Luo, J Wu, W Xie, Y Zhang, N Xu
Gene expression analysis of The Cancer Genome Atlas (TCGA) breast cancer data set show that miR-20a is upregulated in human breast cancer, especially in triple-negative subtype. Gene Set Enrichment Analysis suggests that miR-20a expression negatively correlates with the autophagy/lysosome pathway. We report here that miR-20a inhibits the basal and nutrient starvation-induced autophagic flux and lysosomal proteolytic activity, increases intracellular reactive oxygen species levels and DNA damage response by targeting several key regulators of autophagy, including BECN1, ATG16L1 and SQSTM1...
June 19, 2017: Oncogene
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