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Genomic instability

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https://www.readbyqxmd.com/read/28544233/bcl6-overexpression-alters-gene-expression-profile-in-a-myeloma-cell-line-and-is-associated-with-decreased-dna-damage-response
#1
Kenichi Tahara, Makiko Takizawa, Arito Yamane, Yohei Osaki, Takuma Ishizaki, Takeki Mitsui, Akihiko Yokohama, Takayuki Saitoh, Norifumi Tsukamoto, Morio Matsumoto, Hirokazu Murakami, Yoshihisa Nojima, Hiroshi Handa
BCL6 attenuates DNA damage response (DDR) through gene repression and facilitates tolerance to genomic instability during immunoglobulin affinity maturation in germinal center (GC) B cells. Although BCL6 expression is repressed through normal differentiation of GC B cells into plasma cells, a recent study showed the ectopic expression of BCL6 in primary multiple myeloma (MM) cells. However, the functional roles of BCL6 in MM cells are largely unknown. Here, we report that overexpression of BCL6 in a MM cell line, KMS12PE, induced transcriptional repression of ataxia telangiectasia mutated (ATM), a DDR signaling kinase, which was associated with a reduction in γH2AX formation after DNA damage...
May 23, 2017: Cancer Science
https://www.readbyqxmd.com/read/28540821/enhancing-radiosensitisation-of-brca2-proficient-and-brca2-deficient-cell-lines-with-hyperthermia-and-parp1-i
#2
Arlene L Oei, Vidhula R Ahire, C M van Leeuwen, Rosemarie Ten Cate, Lukas J A Stalpers, Johannes Crezee, H Petra Kok, Nicolaas A P Franken
Poly(ADP-ribose)polymerase1 (PARP1) is an important enzyme in regulating DNA replication. Inhibition of PARP1 can lead to collapsed DNA forks which subsequently causes genomic instability, making DNA more susceptible in developing fatal DNA double strand breaks. PARP1-induced DNA damage is generally repaired by homologous recombination (HR), in which BRCA2 proteins are essential. Therefore, BRCA2-deficient tumour cells are susceptible to treatment with PARP1-inhibitors (PARP1-i). Recently, BRCA2 was shown to be down-regulated by hyperthermia (HT) temporarily, and this consequently inactivated HR for several hours...
May 19, 2017: International Journal of Hyperthermia
https://www.readbyqxmd.com/read/28540426/genetic-analysis-of-heterogeneous-sub-clones-in-recombinant-chinese-hamster-ovary-cells
#3
Kaiming Chen, Dong Li, Hongwen Li, Bing Li, Jie Li, Lei Huang, Renhao Li, Xiaoqing Xu, Lingxiao Jiang, Cizhong Jiang, Hua Gu, Jianmin Fang
Chinese hamster ovary (CHO) cells have been widely used for production of recombinant proteins and therapeutic antibodies. However, owing to the instability and heterogeneity of CHO cells, the development of stable and high-expression recombinant CHO cell lines is often time-consuming. To investigate the mechanisms associated with heterogeneity in protein productivity, we performed transcriptome analysis on the subclones derived from a stable parental CHO clone. Two high-expression subclones and one low-expression subclone were selected based on their similar genomic background and subjected to RNA-seq analysis...
May 24, 2017: Applied Microbiology and Biotechnology
https://www.readbyqxmd.com/read/28539123/multilevel-genomics-of-colorectal-cancers-with-microsatellite-instability-clinical-impact-of-jak1-mutations-and-consensus-molecular-subtype-1
#4
Anita Sveen, Bjarne Johannessen, Torstein Tengs, Stine A Danielsen, Ina A Eilertsen, Guro E Lind, Kaja C G Berg, Edward Leithe, Leonardo A Meza-Zepeda, Enric Domingo, Ola Myklebost, David Kerr, Ian Tomlinson, Arild Nesbakken, Rolf I Skotheim, Ragnhild A Lothe
BACKGROUND: Approximately 15% of primary colorectal cancers have DNA mismatch repair deficiency, causing a complex genome with thousands of small mutations-the microsatellite instability (MSI) phenotype. We investigated molecular heterogeneity and tumor immunogenicity in relation to clinical endpoints within this distinct subtype of colorectal cancers. METHODS: A total of 333 primary MSI+ colorectal tumors from multiple cohorts were analyzed by multilevel genomics and computational modeling-including mutation profiling, clonality modeling, and neoantigen prediction in a subset of the tumors, as well as gene expression profiling for consensus molecular subtypes (CMS) and immune cell infiltration...
May 24, 2017: Genome Medicine
https://www.readbyqxmd.com/read/28539120/comprehensive-whole-genome-sequence-analyses-yields-novel-genetic-and-structural-insights-for-intellectual-disability
#5
Farah R Zahir, Jill C Mwenifumbo, Hye-Jung E Chun, Emilia L Lim, Clara D M Van Karnebeek, Madeline Couse, Karen L Mungall, Leora Lee, Nancy Makela, Linlea Armstrong, Cornelius F Boerkoel, Sylvie L Langlois, Barbara M McGillivray, Steven J M Jones, Jan M Friedman, Marco A Marra
BACKGROUND: Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients. METHODS: We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches...
May 24, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28537880/biological-effects-and-epidemiological-consequences-of-arsenic-exposure-and-reagents-that-can-ameliorate-arsenic-damage-in-vivo
#6
REVIEW
Chinthalapally V Rao, Sanya Pal, Altaf Mohammed, Mudassir Farooqui, Mark P Doescher, Adam S Asch, Hiroshi Y Yamada
Through contaminated diet, water, and other forms of environmental exposure, arsenic affects human health. There are many U.S. and worldwide "hot spots" where the arsenic level in public water exceeds the maximum exposure limit. The biological effects of chronic arsenic exposure include generation of reactive oxygen species (ROS), leading to oxidative stress and DNA damage, epigenetic DNA modification, induction of genomic instability, and inflammation and immunomodulation, all of which can initiate carcinogenesis...
May 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28537574/mechanisms-of-dna-replication-termination
#7
REVIEW
James M Dewar, Johannes C Walter
Genome duplication is carried out by pairs of replication forks that assemble at origins of replication and then move in opposite directions. DNA replication ends when converging replication forks meet. During this process, which is known as replication termination, DNA synthesis is completed, the replication machinery is disassembled and daughter molecules are resolved. In this Review, we outline the steps that are likely to be common to replication termination in most organisms, namely, fork convergence, synthesis completion, replisome disassembly and decatenation...
May 24, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/28537472/a-novel-role-for-a-glycolytic-pathway-kinase-in-regulating-autophagy-has-implications-in-cancer-therapy
#8
Aileen R Ariosa, Daniel J Klionsky
When it comes to cancer initiation and progression, macroautophagy/autophagy seemingly acts in a contradictory fashion, serving either as a suppressive factor that functions to protect against tumor formation or as a support mechanism that sustains the disease itself through its cytoprotective functions. In tumor suppression, autophagy assists by restricting oxidative stress and curbing genomic instability that could possibly cause oncogenic mutations. However, in certain circumstances, autophagy can also promote cancer by providing nourishment and by limiting stress-response pathways, leading to cancer cell survival and rapid proliferation...
May 24, 2017: Autophagy
https://www.readbyqxmd.com/read/28536860/line-1-methylation-level-and-prognosis-in-pancreas-cancer-pyrosequencing-technology-and-literature-review
#9
Kensuke Yamamura, Keisuke Kosumi, Yoshifumi Baba, Kazuto Harada, Feng Gao, Xiaobo Zhang, Lei Zhou, Yuki Kitano, Kota Arima, Takayoshi Kaida, Hideaki Takeyama, Takaaki Higashi, Katsunori Imai, Daisuke Hashimoto, Akira Chikamoto, Xiaodong Tan, Hideo Baba
PURPOSE: Global DNA hypomethylation plays an important role in genomic instability and carcinogenesis. The long interspersed nucleotide element-1 (LINE-1) methylation level is a good surrogate marker of the global DNA methylation level. Previously, we demonstrated a strong relationship between LINE-1 hypomethylation and poor prognosis in certain cancers. However, the relationship between the LINE-1 methylation level and the clinical outcome of pancreatic cancer (PC) remains unclear. METHODS: We used a pyrosequencing assay to measure LINE-1 methylation levels in 126 samples of resected PC and evaluated the prognostic value of the LINE-1 methylation level...
May 23, 2017: Surgery Today
https://www.readbyqxmd.com/read/28536279/the-damaging-effect-of-passenger-mutations-on-cancer-progression
#10
Christopher McFarland, Julia A Yaglom, Jonathan W Wojtkowiak, Jacob Scott, David L Morse, Michael Y Sherman, Leonid Mirny
Genomic instability and high mutation rates cause cancer to acquire numerous mutations and chromosomal alterations during its somatic evolution, most are termed passengers because they do not confer cancer phenotypes. Evolutionary simulations and cancer genomic studies suggest that mildly deleterious passengers accumulate and can collectively slow cancer progression. Clinical data also suggest an association between passenger load and response to therapeutics, yet no causal link between the effects of passengers and cancer progression has been established...
May 23, 2017: Cancer Research
https://www.readbyqxmd.com/read/28535128/low-and-high-let-ionizing-radiation-induces-delayed-homologous-recombination-that-persists-for-two-weeks-before-resolving
#11
Christopher P Allen, Hirokazu Hirakawa, Nakako Izumi Nakajima, Sophia Moore, Jingyi Nie, Neelam Sharma, Mayumi Sugiura, Yuko Hoki, Ryoko Araki, Masumi Abe, Ryuichi Okayasu, Akira Fujimori, Jac A Nickoloff
Genome instability is a hallmark of cancer cells and dysregulation or defects in DNA repair pathways cause genome instability and are linked to inherited cancer predisposition syndromes. Ionizing radiation can cause immediate effects such as mutation or cell death, observed within hours or a few days after irradiation. Ionizing radiation also induces delayed effects many cell generations after irradiation. Delayed effects include hypermutation, hyper-homologous recombination, chromosome instability and reduced clonogenic survival (delayed death)...
May 23, 2017: Radiation Research
https://www.readbyqxmd.com/read/28532423/the-various-aspects-of-genetic-and-epigenetic-toxicology-testing-methods-and-clinical-applications
#12
REVIEW
Ning Ren, Manar Atyah, Wan-Yong Chen, Chen-Hao Zhou
Genotoxicity refers to the ability of harmful substances to damage genetic information in cells. Being exposed to chemical and biological agents can result in genomic instabilities and/or epigenetic alterations, which translate into a variety of diseases, cancer included. This concise review discusses, from both a genetic and epigenetic point of view, the current detection methods of different agents' genotoxicity, along with their basic and clinical relation to human cancer, chemotherapy, germ cells and stem cells...
May 22, 2017: Journal of Translational Medicine
https://www.readbyqxmd.com/read/28531315/the-interaction-between-cytosine-methylation-and-processes-of-dna-replication-and-repair-shape-the-mutational-landscape-of-cancer-genomes
#13
Rebecca C Poulos, Jake Olivier, Jason W H Wong
Methylated cytosines (5mCs) are frequently mutated in the genome. However, no studies have yet comprehensively analysed mutation-methylation associations across cancer types. Here we analyse 916 cancer genomes, together with tissue type-specific methylation and replication timing data. We describe a strong mutation-methylation association across colorectal cancer subtypes, most interestingly in samples with microsatellite instability (MSI) or Polymerase epsilon (POLE) exonuclease domain mutations. By analysing genomic regions with differential mismatch repair (MMR) efficiency, we suggest a possible role for MMR in the correction of 5mC deamination events, potentially accounting for the high rate of 5mC mutation accumulation in MSI tumours...
May 22, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28528812/convergence-of-genomic-instability-and-schlap1-weathering-the-storm-of-intraductal-carcinoma-of-the-prostate
#14
EDITORIAL
Daniel E Spratt
No abstract text is available yet for this article.
May 18, 2017: European Urology
https://www.readbyqxmd.com/read/28521575/high-frequency-of-de-novo-daz-microdeletion-in-sperm-nuclei-of-subfertile-men-possible-involvement-of-genome-instability-in-idiopathic-male-infertility
#15
Hossein Mozdarani, Pegah Ghoraeian, Sohail Mozdarani, Parvin Fallahi, Anahita Mohseni-Meybodi
The occurrence and diagnosis of Y-chromosome microdeletions, specifically deletions of the DAZ (Deleted in Azoospermia) genes are an important issue in male infertility. Screening Y chromosome microdeletion is mainly done using polymerase chain reaction (PCR) on blood leukocytes. However, there is some evidence indicating that presence of DAZ in somatic cells might not be indicative of its presence in the germ cell lineage. Therefore, a total of 130 men with poor semen quality were examined for presence of DAZ microdeletion in their leukocytes...
May 19, 2017: Human Fertility: Journal of the British Fertility Society
https://www.readbyqxmd.com/read/28521333/drugging-the-cancers-addicted-to-dna-repair
#16
Jac A Nickoloff, Dennie Jones, Suk-Hee Lee, Elizabeth A Williamson, Robert Hromas
Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality)...
November 1, 2017: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/28516305/arsenic-toxicity-and-epimutagenecity-the-new-lineage
#17
REVIEW
Somnath Paul, Pritha Bhattacharjee, Ashok K Giri, Pritha Bhattacharjee
Global methylation pattern regulates the normal functioning of a cell. Research have shown arsenic alter these methylation landscapes within the genome leading to aberrant gene expression and inducts various pathophysiological outcomes. Long interspersed nuclear elements (LINE-1) normally remains inert due to heavy methylation of it's promoters, time and various environmental insults, they lose these methylation signatures and begin retro-transposition that has been associated with genomic instability and cancerous outcomes...
May 17, 2017: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
https://www.readbyqxmd.com/read/28515422/up-regulation-and-nuclear-translocation-of-y-box-binding-protein-1-yb-1-is-linked-to-poor-prognosis-in-erg-negative-prostate-cancer
#18
Asmus Heumann, Özge Kaya, Christoph Burdelski, Claudia Hube-Magg, Martina Kluth, Dagmar S Lang, Ronald Simon, Burkhard Beyer, Imke Thederan, Guido Sauter, Jakob R Izbicki, Andreas M Luebke, Andrea Hinsch, Frank Jacobsen, Corinna Wittmer, Franziska Büscheck, Doris Höflmayer, Sarah Minner, Maria Christina Tsourlakis, Thorsten Schlomm, Waldemar Wilczak
Y-box binding protein 1 (YB-1) is an RNA and DNA binding factor with potential prognostic cancer. To evaluate the clinical impact of YB-1, a tissue microarray with 11,152 prostate cancers was analysed by immunohistochemistry. Cytoplasmic and nuclear staining was separately analysed. Cytoplasmic YB-1 was absent or weak in normal epithelium but seen in 86,3% of carcinomas. Cytoplasmic staining was weak, moderate, and strong in 29.6%, 43.7% and 13.0% of tumours and was accompanied by nuclear YB-1 staining in 32...
May 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28515316/dna-damage-induced-degradation-of-exo1-limits-dna-end-resection-to-ensure-accurate-dna-repair
#19
Nozomi Tomimatsu, Bipasha Mukherjee, Janelle Louise Harris, Francesca Ludovica Boffo, Molly Hardebeck, Patrick Ryan Potts, Kum Kum Khanna, Sandeep Burma
End resection of DNA double-strand breaks (DSBs) to generate 3'-single-stranded DNA facilitates DSB repair via error-free homologous recombination (HR) while stymieing repair by the error-prone non-homologous end joining (NHEJ) pathway. Activation of DNA end resection involves phosphorylation of the 5' to 3' exonuclease EXO1 by the phosphoinositide 3-kinase-like kinases ATM and ATR, and by the cyclin-dependent kinases 1 and 2. After activation, EXO1 must also be restrained in order to prevent over-resection which is known to hamper optimal HR and trigger global genomic instability...
May 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28515154/progerin-sequestration-of-pcna-promotes-replication-fork-collapse-and-mislocalization-of-xpa-in-laminopathy-related-progeroid-syndromes
#20
Benjamin A Hilton, Ji Liu, Brian M Cartwright, Yiyong Liu, Maya Breitman, Youjie Wang, Rowdy Jones, Hui Tang, Antonio Rusinol, Phillip R Musich, Yue Zou
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the LMNA gene resulting in production of a truncated farnesylated-prelamin A protein (progerin). We previously reported that XPA mislocalized to the progerin-induced DNA double-strand break (DSB) sites, blocking DSB repair, which led to DSB accumulation, DNA damage responses, and early replication arrest in HGPS. In this study, the XPA mislocalization to DSBs occurred at stalled or collapsed replication forks, concurrent with a significant loss of PCNA at the forks, whereas PCNA efficiently bound to progerin...
May 17, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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