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DNA damage chromosome translocation

Patrick H Maxwell
BACKGROUND: Accumulation of DNA damage, mutations, and chromosomal abnormalities is associated with aging in many organisms. How directly various forms of genomic instability contribute to lifespan in different aging contexts is still under active investigation. Testing whether treatments that alter lifespan change mutation rates early during lifespan could provide support for genomic instability being at least partly responsible for changes in the rates of aging. RESULTS: Rates of mutations, direct repeat recombination, or retrotransposition were measured in young cell populations from two strain backgrounds of Saccharomyces cerevisiae exposed to several growth conditions that shortened or extended yeast chronological lifespan...
October 21, 2016: BMC Genetics
Kit I Tong, Kazushige Ota, Akiyoshi Komuro, Takeshi Ueda, Akihiko Ito, C Anne Koch, Hitoshi Okada
Therapy-related cancers are potentially fatal late life complications for patients who received radio- or chemotherapy. So far, the mouse model showing reduction or delay of these diseases has not been described. We found that the disruption of Aplf in mice moderately attenuated DNA damage repair and, unexpectedly, impeded myeloid neoplasms after exposure to ionizing radiation (IR). Irradiated mutant mice showed higher rates of p53-dependent cell death, fewer chromosomal translocations, and a delay in malignancy-induce;/- mice...
October 6, 2016: Cell Death & Disease
Takahiro Kishikawa, Motoyuki Otsuka, Takeshi Yoshikawa, Motoko Ohno, Hideaki Ijichi, Kazuhiko Koike
Highly repetitive tandem arrays at the centromeric and pericentromeric regions in chromosomes, previously considered silent, are actively transcribed, particularly in cancer. This aberrant expression occurs even in K-ras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To examine the biological roles of the satellite RNAs in carcinogenesis, we construct mouse PanIN-derived cells expressing major satellite (MajSAT) RNA and show increased malignant properties. We find an increase in frequency of chromosomal instability and point mutations in both genomic and mitochondrial DNA...
2016: Nature Communications
Katarina Ochodnicka-Mackovicova, Mahnoush Bahjat, Chiel Maas, Amélie van der Veen, Timon A Bloedjes, Alexander M de Bruin, Harmen van Andel, Carol E Schrader, Rudi W Hendriks, Els Verhoeyen, Richard J Bende, Carel J M van Noesel, Jeroen E J Guikema
The recombination activating gene (RAG) 1 and RAG2 protein complex introduces DNA breaks at Tcr and Ig gene segments that are required for V(D)J recombination in developing lymphocytes. Proper regulation of RAG1/2 expression safeguards the ordered assembly of Ag receptors and the development of lymphocytes, while minimizing the risk for collateral damage. The ataxia telangiectasia mutated (ATM) kinase is involved in the repair of RAG1/2-mediated DNA breaks and prevents their propagation. The simultaneous occurrence of RAG1/2-dependent and -independent DNA breaks in developing lymphocytes exposed to genotoxic stress increases the risk for aberrant recombinations...
October 1, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Ewa Wiland, Monika Fraczek, Marta Olszewska, Maciej Kurpisz
Several studies have shown that the 'poor' sperm DNA quality appears to be an important factor affecting male reproductive ability. In the case of sperm cells from males with the correct somatic karyotype but with deficient spermatogenesis, resulting in a high degree of sperm DNA fragmentation, we observed changes in the preferential topology of the chromosome 7, 9, 15, 18, X and Y centromeres. The changes occurred in radial localization and may have been directly linked to the sperm chromatin damage. This conclusion is mainly based on a comparison of FISH signals that were observed simultaneously in the TUNEL-positive and TUNEL-negative sperm cells...
2016: Scientific Reports
Brian McStay
Nucleoli form around tandem arrays of a ribosomal gene repeat, termed nucleolar organizer regions (NORs). During metaphase, active NORs adopt a characteristic undercondensed morphology. Recent evidence indicates that the HMG-box-containing DNA-binding protein UBF (upstream binding factor) is directly responsible for this morphology and provides a mitotic bookmark to ensure rapid nucleolar formation beginning in telophase in human cells. This is likely to be a widely employed strategy, as UBF is present throughout metazoans...
July 15, 2016: Genes & Development
Lili Wang, Li He, Guoqiang Bao, Xin He, Saijun Fan, Haichao Wang
OBJECTIVE: A nucleosomal protein, HMGB1, can be secreted by activated immune cells or passively released by dying cells, thereby amplifying rigorous inflammatory responses. In this study we aimed to test the possibility that ionizing radiation similarly induces cytoplasmic HMGB1 translocation and extracellular release. METHOD: Human skin fibroblast (GM0639) and bronchial epithelial (16HBE) cells and animals (rats) were exposed to X-ray radiation, and HMGB1 translocation and release were assessed by immunocytochemistry and immunoassay, respectively...
March 2016: Guo Ji Fang She Yi Xue He Yi Xue za Zhi, International Journal of Radiation Medicine and Nuclear Medicine
Agnes Schipler, Veronika Mladenova, Aashish Soni, Vladimir Nikolov, Janapriya Saha, Emil Mladenov, George Iliakis
Chromosome translocations are hallmark of cancer and of radiation-induced cell killing, reflecting joining of incongruent DNA-ends that alter the genome. Translocation-formation requires DNA end-joining mechanisms and incompletely characterized, permissive chromatin conditions. We show that chromatin destabilization by clusters of DNA double-strand-breaks (DSBs) generated by the I-SceI meganuclease at multiple, appropriately engineered genomic sites, compromises c-NHEJ and markedly increases cell killing and translocation-formation compared to single-DSBs...
September 19, 2016: Nucleic Acids Research
Judith W J Bergs, Arlene L Oei, Rosemarie Ten Cate, Hans M Rodermond, Lukas J Stalpers, Gerrit W Barendsen, Nicolaas A P Franken
Hyperthermia can transiently degrade BRCA2 and thereby inhibit the homologous recombination pathway. Induced DNA-double strand breaks (DSB) then have to be repaired via the error prone non-homologous end-joining pathway. In the present study, to investigate the role of hyperthermia in genotoxicity and radiosensitization, the induction of chromosomal aberrations was examined by premature chromosome condensation and fluorescence in situ hybridisation (PCC-FISH), and cell survival was determined by clonogenic assay shortly (0-1 h) and 24 h following exposure to hyperthermia in combination with ionizing radiation...
July 2016: International Journal of Molecular Medicine
Gordon K Livingston, Igor K Khvostunov, Eric Gregoire, Joan-Francesc Barquinero, Lin Shi, Satoshi Tashiro
The purpose of this study was to compare cytogenetic data in a patient before and after treatment with radioiodine to evaluate the assays in the context of biological dosimetry. We studied a 34-year-old male patient who underwent a total thyroidectomy followed by ablation therapy with (131)I (19.28 GBq) for a papillary thyroid carcinoma. The patient provided blood samples before treatment and then serial samples at monthly intervals during the first year period and quarterly intervals for 5 years and finally 20 years after treatment...
May 2016: Radiation and Environmental Biophysics
Maki Morishita, Tomoki Muramatsu, Yumiko Suto, Momoki Hirai, Teruaki Konishi, Shin Hayashi, Daichi Shigemizu, Tatsuhiko Tsunoda, Keiji Moriyama, Johji Inazawa
Chromothripsis is the massive but highly localized chromosomal rearrangement in response to a one-step catastrophic event, rather than an accumulation of a series of subsequent and random alterations. Chromothripsis occurs commonly in various human cancers and is thought to be associated with increased malignancy and carcinogenesis. However, the causes and consequences of chromothripsis remain unclear. Therefore, to identify the mechanism underlying the generation of chromothripsis, we investigated whether chromothripsis could be artificially induced by ionizing radiation...
March 1, 2016: Oncotarget
Jing Wang, Chenhui Ding, Yongming Zhang, Zhimin Zeng, Xuerong Hou, Baomin Lu, Yanwen Xu, Canquan Zhou
OBJECTIVE: To provide preimplantation genetic diagnosis(PGD) for two couples carrying thalassemia mutations and chromosomal abnormalities. METHODS: Couple 1 were both carriers of β 41/42 thalassemia mutations, while the husband has carried a reciprocal translocation with a karyotype of 46,XY,inv(9)(p11;q13),t(11;22)(q25;q13). Couple 2 were both carriers of α (-SEA) thalassemia mutation. Their chromosome karyotypes were both normal, but had two spontaneous abortions...
February 2016: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Guangqing Lu, Jinzhi Duan, Sheng Shu, Xuxiang Wang, Linlin Gao, Jing Guo, Yu Zhang
In eukaryotes, DNA double-strand breaks (DSBs), one of the most harmful types of DNA damage, are repaired by homologous repair (HR) and nonhomologous end-joining (NHEJ). Surprisingly, in cells deficient for core classic NHEJ factors such as DNA ligase IV (Lig4), substantial end-joining activities have been observed in various situations, suggesting the existence of alternative end-joining (A-EJ) activities. Several putative A-EJ factors have been proposed, although results are mostly controversial. By using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system, we generated mouse CH12F3 cell lines in which, in addition to Lig4, either Lig1 or nuclear Lig3, representing the cells containing a single DNA ligase (Lig3 or Lig1, respectively) in their nucleus, was completely ablated...
February 2, 2016: Proceedings of the National Academy of Sciences of the United States of America
Zhangguo Chen, Mihret T Elos, Sawanee S Viboolsittiseri, Katherine Gowan, Sonia M Leach, Michael Rice, Maxwell D Eder, Kenneth Jones, Jing H Wang
BACKGROUND: Activated B lymphocytes harbor programmed DNA double-strand breaks (DSBs) initiated by activation-induced deaminase (AID) and repaired by non-homologous end-joining (NHEJ). While it has been proposed that these DSBs during secondary antibody gene diversification are the primary source of chromosomal translocations in germinal center (GC)-derived B cell lymphomas, this point has not been directly addressed due to the lack of proper mouse models. METHODS: In the current study, we establish a unique mouse model by specifically deleting a NHEJ gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in GC B cells, which results in the spontaneous development of B cell lymphomas that possess features of GC B cells...
January 7, 2016: Journal of Hematology & Oncology
Susanne Lorenz, Tale Barøy, Jinchang Sun, Torfinn Nome, Daniel Vodák, Jan-Christian Bryne, Anne-Mari Håkelien, Lynnette Fernandez-Cuesta, Birte Möhlendick, Harald Rieder, Karoly Szuhai, Olga Zaikova, Terje C Ahlquist, Gard O S Thomassen, Rolf I Skotheim, Ragnhild A Lothe, Patrick S Tarpey, Peter Campbell, Adrienne Flanagan, Ola Myklebost, Leonardo A Meza-Zepeda
In contrast to many other sarcoma subtypes, the chaotic karyotypes of osteosarcoma have precluded the identification of pathognomonic translocations. We here report hundreds of genomic rearrangements in osteosarcoma cell lines, showing clear characteristics of microhomology-mediated break-induced replication (MMBIR) and end-joining repair (MMEJ) mechanisms. However, at RNA level, the majority of the fused transcripts did not correspond to genomic rearrangements, suggesting the involvement of trans-splicing, which was further supported by typical trans-splicing characteristics...
February 2, 2016: Oncotarget
Mai Nanya, Masaki Sato, Kousuke Tanimoto, Minoru Tozuka, Shuki Mizutani, Masatoshi Takagi
Etoposide, a topoisomerase 2 (TOP2) inhibitor, is associated with the development of KMT2A (MLL)-rearranged infant leukemia. An epidemiological study suggested that in utero exposure to TOP2 inhibitors may be involved in generation of KMT2A (MLL) rearrangement. The present study examined the mechanism underlying the development of KMT2A (MLL)-rearranged infant leukemia in response to in utero exposure to etoposide in a mouse model. Fetal liver hematopoietic stem cells were more susceptible to etoposide than maternal bone marrow mononuclear cells...
2015: PloS One
April C L Bostian, Leena Maddukuri, Megan R Reed, Tatsiana Savenka, Jessica H Hartman, Lauren Davis, Dakota L Pouncey, Grover P Miller, Robert L Eoff
Overexpression of the translesion synthesis polymerase hpol κ in glioblastomas has been linked to poor patient prognosis; however, the mechanism promoting higher expression in these tumors remains unknown. We determined that activation of the aryl hydrocarbon receptor (AhR) pathway in glioblastoma cells leads to increased hpol κ mRNA and protein levels. We blocked nuclear translocation and DNA binding by AhR in glioblastoma cells using a small-molecule and observed decreased hpol κ expression. Pharmacological inhibition of tryptophan-2,3-dioxygenase (TDO), the enzyme largely responsible for activating AhR in glioblastoma, led to a decrease in the endogenous AhR agonist kynurenine and a corresponding decrease in hpol κ protein levels...
January 19, 2016: Chemical Research in Toxicology
Arnold Y Seo, Christiaan Leeuwenburgh
Late-life aging in humans is often associated with severe frailty. This suggests catastrophic events reaching an undeniable biological threshold in cellular stability and a rapidly diminished homeostasis. The driving force of the syndrome is likely 'genetic instability' or 'genomic instability', a high frequency of mutations and deletions within the genome (both nuclear and mitochondrial DNA) of bodily somatic cells caused by DNA damage and inefficient repair. Reactive oxygen species, calcium deregulation, and iron dyshomeostasis are potential chemical triggers of nucleic acid sequence alterations and chromosomal rearrangements...
2015: Nestlé Nutrition Institute Workshop Series
Jeffrey M Cloutier, Shantha K Mahadevaiah, Elias ElInati, André Nussenzweig, Attila Tóth, James M A Turner
Chromosome abnormalities are common in the human population, causing germ cell loss at meiotic prophase I and infertility. The mechanisms driving this loss are unknown, but persistent meiotic DNA damage and asynapsis may be triggers. Here we investigate the contribution of these lesions to oocyte elimination in mice with chromosome abnormalities, e.g. Turner syndrome (XO) and translocations. We show that asynapsed chromosomes trigger oocyte elimination at diplonema, which is linked to the presence of phosphorylated H2AFX (γH2AFX)...
October 2015: PLoS Genetics
Marco Fidaleo, Francesca Svetoni, Elisabetta Volpe, Belén Miñana, Daniela Caporossi, Maria Paola Paronetto
Alternative splicing plays a key role in the DNA damage response and in cancer. Ewing Sarcomas (ES) are aggressive tumors caused by different chromosomal translocations that yield in-frame fusion proteins driving transformation. RNA profiling reveals genes differentially regulated by UV light irradiation in two ES cell lines exhibiting different sensitivity to genotoxic stress. In particular, irradiation induces a new isoform of the RNA helicase DHX9 in the more sensitive SK-N-MC cells, which is targeted to nonsense-mediated decay (NMD), causing its downregulation...
October 13, 2015: Oncotarget
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