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ataxia telangiectasia mutated

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https://www.readbyqxmd.com/read/28076792/the-mre11-nbs1-interface-is-essential-for-viability-and-tumor-suppression
#1
Jun Hyun Kim, Malgorzata Grosbart, Roopesh Anand, Claire Wyman, Petr Cejka, John H J Petrini
The Mre11 complex (Mre11, Rad50, and Nbs1) is integral to both DNA repair and ataxia telangiectasia mutated (ATM)-dependent DNA damage signaling. All three Mre11 complex components are essential for viability at the cellular and organismal levels. To delineate essential and non-essential Mre11 complex functions that are mediated by Nbs1, we used TALEN-based genome editing to derive Nbs1 mutant mice (Nbs1(mid) mice), which harbor mutations in the Mre11 interaction domain of Nbs1. Nbs1(mid) alleles that abolished interaction were incompatible with viability...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28074659/ferulic-acid-fa-abrogates-%C3%AE-radiation-induced-oxidative-stress-and-dna-damage-by-up-regulating-nuclear-translocation-of-nrf2-and-activation-of-nhej-pathway
#2
Ujjal Das, Krishnendu Manna, Amitava Khan, Mahuya Sinha, Sushobhan Biswas, Aaveri Sengupta, Anindita Chakraborty, Sanjit Dey
The present study was aimed to evaluate the radioprotective effect of ferulic acid (FA), a naturally occurring plant flavonoid in terms of DNA damage and damage related alterations of repair pathways by gamma radiation. FA was administered at a dose of 50 mg/kg body weight for five consecutive days prior to exposing the swiss albino mice to a single dose of 10 Gy gamma radiation. Ionising radiation induces oxidative damage manifested by decreased expression of Cu, Zn-SOD (SOD stands for super oxide dismutase), Mn-SOD and catalase...
January 11, 2017: Free Radical Research
https://www.readbyqxmd.com/read/28062495/therapeutic-targeting-of-rna-polymerase-i-with-the-small-molecule-cx-5461-for-prevention-of-arterial-injury-induced-neointimal-hyperplasia
#3
Qing Ye, Shu Pang, Wenjing Zhang, Xiaotong Guo, Jianli Wang, Yongtao Zhang, Yang Liu, Xiao Wu, Fan Jiang
OBJECTIVE: RNA polymerase I (Pol I)-dependent rRNA synthesis is a determinant factor in ribosome biogenesis and thus cell proliferation. The importance of dysregulated Pol I activity in cardiovascular disease, however, has not been recognized. Here, we tested the hypothesis that specific inhibition of Pol I might prevent arterial injury-induced neointimal hyperplasia. APPROACH AND RESULTS: CX-5461 is a novel selective Pol I inhibitor. Using this tool, we demonstrated that local inhibition of Pol I blocked balloon injury-induced neointima formation in rat carotid arteries in vivo...
January 5, 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28057860/contribution-of-canonical-nonhomologous-end-joining-to-chromosomal-rearrangements-is-enhanced-by-atm-kinase-deficiency
#4
Ragini Bhargava, Caree R Carson, Gabriella Lee, Jeremy M Stark
A likely mechanism of chromosomal rearrangement formation involves joining the ends from two different chromosomal double-strand breaks (DSBs). These events could potentially be mediated by either of two end-joining (EJ) repair pathways [canonical nonhomologous end joining (C-NHEJ) or alternative end joining (ALT-EJ)], which cause distinct rearrangement junction patterns. The relative role of these EJ pathways during rearrangement formation has remained controversial. Along these lines, we have tested whether the DNA damage response mediated by the Ataxia Telangiectasia Mutated (ATM) kinase may affect the relative influence of C-NHEJ vs...
January 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28045107/collateral-damage-insights-into-bacterial-mechanisms-that-predispose-host-cells-to-cancer
#5
Aurélie Gagnaire, Bertrand Nadel, Didier Raoult, Jacques Neefjes, Jean-Pierre Gorvel
Infections are estimated to contribute to 20% of all human tumours. Viruses are known to induce cell transformation, but evidence has also linked bacteria, such as Helicobacter pylori and Salmonella enterica subsp. enterica serovar Typhi, to different cancer types. In addition, Chlamydia trachomatis, Fusobacterium nucleatum and Bacteroides fragilis are associated with the development of cancer, although a causal relationship has not yet been established. Bacterial effectors such as colibactin and the virulence factor cytotoxin-associated gene A (CagA) can promote cancer directly by influencing host cell signalling cascades, such as the WNT and ataxia-telangiectasia mutated (ATM) pathways, or indirectly by inducing tissue damage and inflammatory responses...
January 3, 2017: Nature Reviews. Microbiology
https://www.readbyqxmd.com/read/28017939/huntingtin-is-a-scaffolding-protein-in-the-atm-oxidative-dna-damage-response-complex
#6
Tamara Maiuri, Andrew J Mocle, Claudia L Hung, Jianrun Xia, Willeke M C van Roon-Mom, Ray Truant
Huntington's disease (HD) is an age-dependent neurodegenerative disease. DNA repair pathways have recently been implicated as the most predominant modifiers of age of onset in HD patients. We report that endogenous huntingtin protein directly participates in oxidative DNA damage repair. Using novel chromobodies to detect endogenous human huntingtin in live cells, we show that localization of huntingtin to DNA damage sites is dependent on the kinase activity of ataxia telangiectasia mutated (ATM) protein. Super-resolution microscopy and biochemical assays revealed that huntingtin co-localizes with and scaffolds proteins of the DNA damage response pathway in response to oxidative stress...
December 25, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28012797/ataxia-telangiectasia-mutated-interactor-regulates-head-and-neck-cancer-metastasis-via-kras-expression
#7
Yue-Ju Li, Wei-Ting Lai, Cheng-Chi Chang, Mark Yen-Ping Kuo, Yi-Ting Deng, Cheng-Ning Yang, Shih-Jung Cheng, Tai-Sheng Wu, Szu-Ta Chen, Been-Ren Lin
OBJECTIVES: Relapse is the most serious problem affecting the morbidity and mortality rates of patients with head and neck squamous cell carcinoma (HNSCC). Although HNSCC has been studied for several decades, the exact mechanism of cancer recurrence remains unclear. MATERIALS AND METHODS: ataxia-telangiectasia mutated interactor (ATMIN) messenger RNA(mRNA) expression was detected in HNSCC samples by quantitative RT-PCR, and was analyzed with patients' clinical outcomes by Kaplan-Meier analyses...
December 21, 2016: Oral Oncology
https://www.readbyqxmd.com/read/28009280/three-dimensional-architecture-of-the-human-brca1-a-histone-deubiquitinase-core-complex
#8
Otto J P Kyrieleis, Pauline B McIntosh, Sarah R Webb, Lesley J Calder, Janette Lloyd, Nisha A Patel, Stephen R Martin, Carol V Robinson, Peter B Rosenthal, Stephen J Smerdon
BRCA1 is a tumor suppressor found to be mutated in hereditary breast and ovarian cancer and plays key roles in the maintenance of genomic stability by homologous recombination repair. It is recruited to damaged chromatin as a component of the BRCA1-A deubiquitinase, which cleaves K63-linked ubiquitin chains attached to histone H2A and H2AX. BRCA1-A contributes to checkpoint regulation, repair pathway choice, and HR repair efficiency through molecular mechanisms that remain largely obscure. The structure of an active core complex comprising two Abraxas/BRCC36/BRCC45/MERIT40 tetramers determined by negative-stain electron microscopy (EM) reveals a distorted V-shape architecture in which a dimer of Abraxas/BRCC36 heterodimers sits at the base, with BRCC45/Merit40 pairs occupying each arm...
December 20, 2016: Cell Reports
https://www.readbyqxmd.com/read/28007901/a-rat-model-of-ataxia-telangiectasia-evidence-for-a-neurodegenerative-phenotype
#9
Hazel Quek, John Luff, KaGeen Cheung, Sergei Kozlov, Magtouf Gatei, C Soon Lee, Mark C Bellingham, Peter G Noakes, Yi Chieh Lim, Nigel L Barnett, Steven Dingwall, Ernst Wolvetang, Tomoji Mashimo, Tara L Roberts, Martin F Lavin
Ataxia-telangiectasia (A-T), an autosomal recessive disease caused by mutations in the ATM gene is characterised by cerebellar atrophy and progressive neurodegeneration which has been poorly recapitulated in Atm mutant mice. Consequently, pathways leading to neurodegeneration in A-T are poorly understood. We describe here the generation of an Atm knockout rat model that does not display cerebellar atrophy but instead paralysis and spinal cord atrophy, reminiscent of that seen in older patients and milder forms of the disorder...
December 22, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28005419/aging-of-the-immune-system-mechanisms-and-therapeutic-targets
#10
Cornelia M Weyand, Jörg J Goronzy
Beginning with the sixth decade of life, the human immune system undergoes dramatic aging-related changes, which continuously progress to a state of immunosenescence. The aging immune system loses the ability to protect against infections and cancer and fails to support appropriate wound healing. Vaccine responses are typically impaired in older individuals. Conversely, inflammatory responses mediated by the innate immune system gain in intensity and duration, rendering older individuals susceptible to tissue-damaging immunity and inflammatory disease...
December 2016: Annals of the American Thoracic Society
https://www.readbyqxmd.com/read/27988859/atm-mutations-for-surgeons
#11
Sara A Mansfield, Robert Pilarski, Doreen M Agnese
The ataxia-telangiectasia mutated (ATM) gene encodes a protein kinase involved in DNA repair. Heterozygotic carriers are at an increased risk of developing breast cancer. As the use of genetic testing increases, identification of at-risk patients will also increase. The aim of this study is to review two cases of heterozygous ATM mutation carriers and review the literature to clarify the cancer risks and suggested management for breast surgeons who will be intimately involved in the care of these patients.
December 17, 2016: Familial Cancer
https://www.readbyqxmd.com/read/27984128/dna-damage-response-in-nephrotoxic-and-ischemic-kidney-injury
#12
REVIEW
Mingjuan Yan, Chengyuan Tang, Zhengwei Ma, Shuang Huang, Zheng Dong
DNA damage activates specific cell signaling cascades for DNA repair, cell cycle arrest, senescence, and/or cell death. Recent studies have demonstrated DNA damage response (DDR) in experimental models of acute kidney injury (AKI). In cisplatin-induced AKI or nephrotoxicity, the DDR pathway of ATR/Chk2/p53 is activated and contributes to renal tubular cell apoptosis. In ischemic AKI, DDR seems more complex and involves at least the ataxia telangiectasia mutated (ATM), a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, and p53; however, while ATM may promote DNA repair, p53 may trigger cell death...
October 27, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/27982097/induction-of-a-cellular-dna-damage-response-by-porcine-circovirus-type-2-facilitates-viral-replication-and-mediates-apoptotic-responses
#13
Li Wei, Shanshan Zhu, Jing Wang, Rong Quan, Xu Yan, Zixue Li, Lei Hou, Naidong Wang, Yi Yang, Haijun Jiang, Jue Liu
Cellular DNA damage response (DDR) triggered by infection of DNA viruses mediate cell cycle checkpoint activation, DNA repair, or apoptosis induction. In the present study, infection of porcine circovirus type 2 (PCV2), which serves as a major etiological agent of PCV2-associated diseases (PCVAD), was found to elicit a DNA damage response (DDR) as observed by the phosphorylation of H2AX and RPA32 following infection. The response requires active viral replication, and all the ATM (ataxia telangiectasia-mutated kinase), ATR (ATM- and Rad3-related kinase), and DNA-PK (DNA-dependent protein kinase) are the transducers of the DDR signaling events in the PCV2-infected cells as demonstrated by the phosphorylation of ATM, ATR, and DNA-PK signalings as well as reductions in their activations after treatment with specific kinase inhibitors...
December 16, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27980111/dna-pkcs-atm-and-atr-interplay-maintains-genome-integrity-during-neurogenesis
#14
Vanessa Enriquez-Rios, Lavinia C Dumitrache, Susanna M Downing, Yang Li, Eric J Brown, Helen R Russell, Peter J McKinnon
: The DNA damage response (DDR) orchestrates a network of cellular processes that integrates cell-cycle control and DNA repair or apoptosis, which serves to maintain genome stability. DNA-PKcs (the catalytic subunit of the DNA-dependent kinase, encoded by PRKDC), ATM (ataxia telangiectasia, mutated) and ATR (ATM and Rad3 related) are related PI3K-like protein kinases and central regulators of the DDR. Defects in these kinases have been linked to neurodegenerative or neurodevelopmental syndromes...
December 15, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27979966/insulin-like-growth-factor-1-receptor-signaling-is-required-for-optimal-atr-chk1-kinase-signaling-in-uvb-irradiated-human-keratinocytes
#15
Michael G Kemp, Dan F Spandau, Richard Simman, Jeffrey B Travers
Ultraviolet B (UVB) wavelengths of light induce the formation of photoproducts in DNA that are potentially mutagenic if not properly removed by the nucleotide excision repair machinery. As an additional mechanism to minimize the risk of mutagenesis, UVB-irradiated cells also activate a checkpoint signaling cascade mediated by the ATR (ataxia telangiectasia-mutated and rad3-related) and CHK1 (checkpoint kinase 1) kinases to transiently suppress DNA synthesis and cell cycle progression. Given that keratinocytes in geriatric skin display reduced activation of the insulin-like growth factor-1 receptor (IGF-1) and alterations in DNA repair rate, apoptosis, and senescence following UVB exposure, here we used cultured human keratinocytes in vitro and skin explants ex vivo to examine how IGF-1R activation status affects ATR-CHK1 kinase signaling and the inhibition of DNA replication following UVB irradiation...
December 15, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27965933/colorectal-choriocarcinoma-in-a-patient-with-probable-lynch-syndrome
#16
Viktor H Koelzer, Karl Steuer, Ulrike Camenisch Gross, Dieter Zimmermann, Aino Paasinen-Sohns, Kirsten D Mertz, Gieri Cathomas
BACKGROUND: Personalized therapy of colorectal cancer is influenced by morphological, molecular, and host-related factors. Here, we report the comprehensive clinicopathological and molecular analysis of an extra-gestational colorectal choriocarcinoma in a patient with probable Lynch syndrome. CASE PRESENTATION: A 61-year-old female with history of gastric cancer at age 36 presented with a transmurally invasive tumor of the right hemicolon and liver metastasis. A right hemicolectomy was performed...
2016: Frontiers in Oncology
https://www.readbyqxmd.com/read/27959407/low-dose-irradiation-promotes-proliferation-of-the-human-breast-cancer-mda-mb-231-cells-through-accumulation-of-mutant-p53
#17
Si-Jie Li, Xin-Yue Liang, Hai-Jun Li, Wei Li, Lei Zhou, Hua-Qiu Chen, Song-Gen Ye, De-Hai Yu, Jiu-Wei Cui
Low-dose irradiation (LDIR) has been proven to have differential biological effects on normal mammalian somatic cells and cancer cells. Our previous study showed that p53 gene status is a critical factor regulating the effect of LDIR on cancer cells. We investigated the effect of LDIR on the breast cancer cell line MDA-MB-231 that harbors a mutant p53 gene, and the normal breast fibroblast cell line Hs 578Bst. In the present study, we showed that 150 mGy LDIR pormoted growth of MDA-MB-231 cells but not Hs 578Bst cells...
January 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/27942472/cutis-tricolor-a-literature-review-and-report-of-five-new-cases
#18
Martino Ruggieri, Agata Polizzi, Carmelo Schepis, Massimiliano Morano, Serena Strano, Giuseppe Belfiore, Stefano Palmucci, Pietro Valerio Foti, Concetta Pirrone, Mario Roggini, Emanule David, Vincenzo Salpietro, Pietro Milone
BACKGROUND: Cutis tricolor is a skin abnormality consisting in a combination of congenital hyper- and hypopigmented skin lesions (in the form of paired macules, patches or streaks) in close proximity to each other in a background of normal skin. It is currently regarded as a twin-spotting (mosaic) phenomenon and today is clear that not all cases of cutis tricolor represent one single entity. This phenomenon has been reported so far either: (I) as an purely cutaneous trait; (II) as a part of a complex malformation phenotype (Ruggieri-Happle syndrome, RHS) including distinct facial features, eye (cataract), skeletal (skull and vertebral defects, and long bones dysplasia), nervous system (corpus callosum, cerebellar and white matter anomalies, cavum vergae and holoprosencephaly) and systemic abnormalities; (III) as a distinct type with multiple, disseminated smaller skin macules (cutis tricolor parvimaculata); and (IV) in association with other skin disturbances [e...
October 2016: Quantitative Imaging in Medicine and Surgery
https://www.readbyqxmd.com/read/27939942/regulation-of-the-dna-damage-response-by-dna-pkcs-inhibitory-phosphorylation-of-atm
#19
Yi Zhou, Ji-Hoon Lee, Wenxia Jiang, Jennie L Crowe, Shan Zha, Tanya T Paull
Ataxia-telangiectasia mutated (ATM) regulates the DNA damage response as well as DNA double-strand break repair through homologous recombination. Here we show that ATM is hyperactive when the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is chemically inhibited or when the DNA-PKcs gene is deleted in human cells. Pre-incubation of ATM protein with active DNA-PKcs also significantly reduces ATM activity in vitro. We characterize several phosphorylation sites in ATM that are targets of DNA-PKcs and show that phospho-mimetic mutations at these residues significantly inhibit ATM activity and impair ATM signaling upon DNA damage...
January 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/27929719/nad-the-convergence-of-dna-repair-and-mitophagy
#20
Evandro F Fang, Vilhelm A Bohr
ATM is a 350 kDa serine/threonine kinase best known for its role in DNA repair and multiple cellular homeostasis pathways. Mutation in ATM causes the disease ataxia telangiectasia (A-T) with clinical features including ataxia, severe cerebellar atrophy and Purkinje cell loss. In a cross-species study, using primary rat neurons, the roundworm C. elegans, and a mouse model of A-T, we showed that loss of ATM induces mitochondrial dysfunction and compromised mitophagy due to NAD(+) insufficiency. Remarkably, NAD(+) repletion mitigates both the DNA repair defect and mitochondrial dysfunction in ATM-deficient neurons...
December 8, 2016: Autophagy
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