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https://www.readbyqxmd.com/read/28076794/brca1-directs-the-repair-pathway-to-homologous-recombination-by-promoting-53bp1-dephosphorylation
#1
Mayu Isono, Atsuko Niimi, Takahiro Oike, Yoshihiko Hagiwara, Hiro Sato, Ryota Sekine, Yukari Yoshida, Shin-Ya Isobe, Chikashi Obuse, Ryotaro Nishi, Elena Petricci, Shinichiro Nakada, Takashi Nakano, Atsushi Shibata
BRCA1 promotes homologous recombination (HR) by activating DNA-end resection. By contrast, 53BP1 forms a barrier that inhibits DNA-end resection. Here, we show that BRCA1 promotes DNA-end resection by relieving the 53BP1-dependent barrier. We show that 53BP1 is phosphorylated by ATM in S/G2 phase, promoting RIF1 recruitment, which inhibits resection. 53BP1 is promptly dephosphorylated and RIF1 released, despite remaining unrepaired DNA double-strand breaks (DSBs). When resection is impaired by CtIP/MRE11 endonuclease inhibition, 53BP1 phosphorylation and RIF1 are sustained due to ongoing ATM signaling...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28057860/contribution-of-canonical-nonhomologous-end-joining-to-chromosomal-rearrangements-is-enhanced-by-atm-kinase-deficiency
#2
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/28052107/ubiquitin-accumulation-on-disease-associated-protein-aggregates-is-correlated-with-nuclear-ubiquitin-depletion-histone-de-ubiquitination-and-impaired-dna-damage-response
#3
Adi Ben Yehuda, Marwa Risheq, Ofra Novoplansky, Kirill Bersuker, Ron R Kopito, Michal Goldberg, Michael Brandeis
Deposition of ubiquitin conjugates on inclusion bodies composed of protein aggregates is a definitive cytopathological hallmark of neurodegenerative diseases. We show that accumulation of ubiquitin on polyQ IB, associated with Huntington's disease, is correlated with extensive depletion of nuclear ubiquitin and histone de-ubiquitination. Histone ubiquitination plays major roles in chromatin regulation and DNA repair. Accordingly, we observe that cells expressing IB fail to respond to radiomimetic DNA damage, to induce gamma-H2AX phosphorylation and to recruit 53BP1 to damaged foci...
2017: PloS One
https://www.readbyqxmd.com/read/28046843/su-f-t-665-confocal-microscopy-imaging-of-cell-cycle-distribution-in-cells-treated-with-pegylated-gold-nanoshells
#4
D Sadetaporn, D Flint, C McFadden, A Asaithamby, G Sawakuchi
PURPOSE: To use confocal microscopy to distinguish cells in different phases of the cell cycle before and after treatment with pegylated gold nanoshells (PEG-AuNSs). METHODS: Transfected fibrosarcoma cells (HT1080-EYFP-53BP1-FUCCI) were cultured in T-25 flasks and seeded in glass bottom dishes. These cells express the fluorescent probe AmCyan during the G2/S phases of the cell cycle, mCherry during the G1 phase, and EYFP tagged to the DNA repair protein 53BP1. After allowing cells 4 h to adhere to dishes, PEG-AuNS (Nanospectra Biosciences, Houston, TX) at a concentration of 0...
June 2016: Medical Physics
https://www.readbyqxmd.com/read/28032817/the-brca1-ubiquitin-ligase-function-sets-a-new-trend-for-remodelling-in-dna-repair
#5
Ruth M Densham, Joanna R Morris
The protein product of the breast and ovarian cancer gene, BRCA1, is part of an obligate heterodimer with BARD1. Together these RING bearing proteins act as an E3 ubiquitin ligase. Several functions have been attributed to BRCA1 that contribute to genome integrity but which of these, if any, require this enzymatic function was unclear. Here we review recent studies clarifying the role of BRCA1 E3 ubiquitin ligase in DNA repair. Perhaps the most surprising finding is the narrow range of BRCA1 functions this activity relates to...
December 29, 2016: Nucleus
https://www.readbyqxmd.com/read/28027584/il6-dependent-genomic-instability-heralds-accelerated-carcinogenesis-following-liver-regeneration-on-a-background-of-chronic-hepatitis
#6
Tali Lanton, Anat Shriki, Yael Nechemia-Arbely, Rinat Abramovitch, Orr Levkovitch, Revital Adar, Nofar Rosenberg, Mor Paldor, Daniel Goldenberg, Amir Sonnenblick, Amnon Peled, Stefan Rose-John, Eithan Galun, Jonathan H Axelrod
: Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality worldwide. For these patients surgical resection is a principal treatment modality that offers a chance of prolonged survival. However, tumor recurrence after resection, the mechanisms of which remain obscure, markedly limits the long-term survival of these patients. We have previously shown that partial hepatectomy (PH) in Mdr2 knockout (Mdr2(-/-) ) mice, a model of chronic inflammation-associated liver cancer, significantly accelerates hepatocarcinogenesis...
December 27, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28017476/double-strand-break-induction-and-kinetics-indicate-preserved-hypersensitivity-in-keratinocytes-to-subtherapeutic-doses-for-7weeks-of-radiotherapy
#7
Fredrik Qvarnström, Martin Simonsson, Jan Nyman, Ingegerd Hermansson, Majlis Book, Karl-Axel Johansson, Ingela Turesson
BACKGROUND AND PURPOSE: Previously we reported that hyper-radiosensitivity (HRS) was evidenced by quantifying DNA double strand break (DSB) foci in epidermis biopsies collected after delivering radiotherapeutic one and five dose fractions. The aim of this study was to determine whether HRS was preserved throughout a 7-week radiotherapy treatment, and also to examine the rate of foci decline and foci persistence between dose fractions. MATERIALS AND METHODS: 42 patients with prostate cancer received 7-week fractionated radiotherapy treatment (RT) with daily dose fractions of 0...
December 22, 2016: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/27999166/the-cytolethal-distending-toxin-produced-by-nontyphoidal-salmonella-serotypes-javiana-montevideo-oranienburg-and-mississippi-induces-dna-damage-in-a-manner-similar-to-that-of-serotype-typhi
#8
Rachel A Miller, Martin Wiedmann
: Select nontyphoidal Salmonella enterica (NTS) serotypes were recently found to encode the Salmonella cytolethal distending toxin (S-CDT), an important virulence factor for serotype Typhi, the causative agent of typhoid fever. Using a PCR-based assay, we determined that among 21 NTS serotypes causing the majority of food-borne salmonellosis cases in the United States, genes encoding S-CDT are conserved in isolates representing serotypes Javiana, Montevideo, and Oranienburg but that among serotype Mississippi isolates, the presence of S-CDT-encoding genes is clade associated...
December 20, 2016: MBio
https://www.readbyqxmd.com/read/27989676/dna-damage-follows-repair-factor-depletion-and-portends-genome-variation-in-cancer-cells-after-pore-migration
#9
Jerome Irianto, Yuntao Xia, Charlotte R Pfeifer, Avathamsa Athirasala, Jiazheng Ji, Cory Alvey, Manu Tewari, Rachel R Bennett, Shane M Harding, Andrea J Liu, Roger A Greenberg, Dennis E Discher
Migration through micron-size constrictions has been seen to rupture the nucleus, release nuclear-localized GFP, and cause localized accumulations of ectopic 53BP1-a DNA repair protein. Here, constricted migration of two human cancer cell types and primary mesenchymal stem cells (MSCs) increases DNA breaks throughout the nucleoplasm as assessed by endogenous damage markers and by electrophoretic "comet" measurements. Migration also causes multiple DNA repair proteins to segregate away from DNA, with cytoplasmic mis-localization sustained for many hours as is relevant to delayed repair...
December 9, 2016: Current Biology: CB
https://www.readbyqxmd.com/read/27982581/comprehensive-landscape-of-nrf2-and-p53-pathway-activation-dynamics-by-oxidative-stress-and-dna-damage
#10
Steven Hiemstra, Marije Niemeijer, Esmee Koedoot, Steven Wink, Janna E Klip, Matthijs Vlasveld, Elisabeth de Zeeuw, Bram van Os, Andrew White, Bob van de Water
A quantitative dynamics pathway map of the Nrf2-mediated oxidative stress response and p53-related DNA damage response pathways as well as the cross-talk between these pathways has not systematically been defined. To allow the dynamic single cell evaluation of these pathways, we have used BAC-GFP recombineering to tag for each pathway's three key components: for the oxidative stress response, Keap1-GFP, Nrf2-GFP, and Srxn1-GFP; for the DNA damage response, 53bp1-GFP, p53-GFP, and p21-GFP. The dynamic activation of these individual components was assessed using quantitative high throughput confocal microscopy after treatment with a broad concentration range of diethyl maleate (DEM; to induce oxidative stress) and etoposide (to induce DNA damage)...
December 16, 2016: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/27967308/a-biallelic-mutation-in-the-homologous-recombination-repair-gene-spidr-is-associated-with-human-gonadal-dysgenesis
#11
Pola Smirin-Yosef, Nehama Zuckerman-Levin, Shay Tzur, Yaron Granot, Lior Cohen, Juliane Sachsenweger, Guntram Borck, Irina Lagovsky, Mali Salmon-Divon, Lisa Wiesmüller, Lina Basel-Vanagaite
CONTEXT: Primary ovarian insufficiency (POI) is caused by ovarian follicle depletion or follicle dysfunction, characterized by amenorrhea with elevated gonadotropin levels. The disorder presents as absence of normal progression of puberty. OBJECTIVE: To elucidate the cause of ovarian dysfunction in a family with POI. DESIGN: We performed whole exome sequencing in two affected individuals. To evaluate whether DNA double-stranded break (DSB) repair activities are altered in biallelic mutation carriers we applied an EGFP-based assay for the detection of specific DSB repair pathways in blood-derived cells...
December 14, 2016: Journal of Clinical Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27941214/calcium-alterations-signal-either-to-senescence-or-to-autophagy-induction-in-stem-cells-upon-oxidative-stress
#12
Aleksandra V Borodkina, Alla N Shatrova, Pavel I Deryabin, Anastasiia A Griukova, Polina A Abushik, Sergei M Antonov, Nikolay N Nikolsky, Elena B Burova
Intracellular calcium ([Ca(2+)]i) has been reported to play an important role in autophagy, apoptosis and necrosis, however, a little is known about its impact in senescence. Here we investigated [Ca(2+)]i contribution to oxidative stress-induced senescence of human endometrium-derived stem cells (hMESCs). In hMESCs sublethal H2O2-treatment resulted in a rapid calcium release from intracellular stores mediated by the activation of PLC/IP3/IP3R pathway. Notably, further senescence development was accompanied by persistently elevated [Ca(2+)]i levels...
December 8, 2016: Aging
https://www.readbyqxmd.com/read/27936985/t-lymphocytes-to-predict-radiation-induced-late-effects-in-normal-tissues
#13
Muriel Brengues, Ariane Lapierre, Céline Bourgier, André Pèlegrin, Mahmut Özsahin, David Azria
Radiotherapy is one of the main treatments for solid tumors. The total dose that can be delivered to the tumor is limited by the radiation amount received by the surrounding normal tissues, which are at risk of developing acute and late radiation-induced effects. Areas covered: Severe late radiation-induced toxicity occurs in 5% to 10% of patients following radiotherapy. However, the current radiotherapy and radiation protection protocols do not take into account the variations in radiosensitivity among individuals...
December 22, 2016: Expert Review of Molecular Diagnostics
https://www.readbyqxmd.com/read/27923209/recognition-of-ubiquitinated-nucleosomes
#14
REVIEW
Michael T Morgan, Cynthia Wolberger
Histone ubiquitination plays a non-degradative role in regulating transcription and the DNA damage response. A mechanistic understanding of this chromatin modification has lagged that of small histone modifications because of the technical challenges in preparing ubiquitinated nucleosomes. The recent structure of the DUB module of the SAGA coactivator complex bound to a nucleosome containing monoubiquitinated H2B has provided the first view of how specialized subunits target this enzyme to its substrate. Single particle electron microscopy of the intact SAGA coactivator suggests how the DUB module and histone acetyltransferase module engage a nucleosomal substrate...
December 3, 2016: Current Opinion in Structural Biology
https://www.readbyqxmd.com/read/27922110/%C3%AE-h2ax-53bp1-pkap-1-foci-and-their-linear-tracks-induced-by-in-vitro-exposure-to-radon-and-its-progeny-in-human-peripheral-blood-lymphocytes
#15
Defang Ding, Yaping Zhang, Jing Wang, Xufei Wang, Dunhuang Fan, Linfeng He, Xuxia Zhang, Yun Gao, Qiang Li, Honghong Chen
The biodosimetric information is critical for evaluating the human health hazards caused by radon and its progeny. Here, we demonstrated that the formation of phosphorylated histone variant H2AX (γ-H2AX), p53-binding protein 1 (53BP1) and phosphorylated KRAB-associated protein 1 (pKAP-1) foci and their linear tracks in human peripheral blood lymphocytes (HPBLs) in vitro exposed to radon and its progeny were dependent on the cumulative absorbed dose of radon exposure but was unrelated to the concentration of radon...
December 6, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27903633/an-e2-guided-e3-screen-identifies-the-rnf17-ube2u-pair-as-regulator-of-the-riddle-syndrome-protein-rnf168
#16
Yingying Guo, Liwei An, Hoi-Man Ng, Shirley M H Sy, Michael S Y Huen
Protein ubiquitination has emerged as pivotal regulatory reactions that promote cellular responses to DNA damage. With a goal to delineate the DNA damage signal transduction cascade, we systematically analysed the human E2 ubiquitin and ubiquitin-like conjugating enzymes for their ability to mobilise the DNA damage marker 53BP1 onto IR-induced DNA double-strand breaks (DSBs). RNAi-based screen identified UBE2U as a candidate regulator of chromatin responses at DSBs. Further mining of the UBE2U interactome uncovered its cognate E3 RNF17 as a novel factor that, via the Riddle syndrome protein RNF168, enforces DNA damage responses...
November 30, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27899080/erratum-to-53bp1-depletion-causes-parp-inhibitor-resistance-in-atm-deficient-breast-cancer-cells
#17
Ruoxi Hong, Fei Ma, Weimin Zhang, Xiying Yu, Qing Li, Yang Luo, Changjun Zhu, Binghe Xu, Wei Jiang
No abstract text is available yet for this article.
November 30, 2016: BMC Cancer
https://www.readbyqxmd.com/read/27893463/inhibition-of-the-gas6-axl-pathway-augments-the-efficacy-of-chemotherapies
#18
Mihalis S Kariolis, Yu Rebecca Miao, Anh Diep, Shannon E Nash, Monica M Olcina, Dadi Jiang, Douglas S Jones, Shiven Kapur, Irimpan I Mathews, Albert C Koong, Erinn B Rankin, Jennifer R Cochran, Amato J Giaccia
The AXL receptor and its activating ligand, growth arrest-specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. However, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. Here, we have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6...
January 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27866833/tp53-and-53bp1-reunited
#19
Thierry Soussi, Guido Kroemer
Identified as a TP53-binding protein, 53BP1 is a key regulator of the cellular response to double-strand breaks, a TP53-independent activity. Recent data have established a new TP53-dependent function for 53BP1 in mitotic surveillance after centrosome loss.
November 17, 2016: Trends in Cell Biology
https://www.readbyqxmd.com/read/27849008/ku70-serine-155-mediates-aurora-b-inhibition-and-activation-of-the-dna-damage-response
#20
Victoria L Fell, Elizabeth A Walden, Sarah M Hoffer, Stephanie R Rogers, Amelia S Aitken, Louisa M Salemi, Caroline Schild-Poulter
The Ku heterodimer (Ku70/Ku80) is the central DNA binding component of the classical non-homologous end joining (NHEJ) pathway that repairs DNA double-stranded breaks (DSBs), serving as the scaffold for the formation of the NHEJ complex. Here we show that Ku70 is phosphorylated on Serine 155 in response to DNA damage. Expression of Ku70 bearing a S155 phosphomimetic substitution (Ku70 S155D) in Ku70-deficient mouse embryonic fibroblasts (MEFs) triggered cell cycle arrest at multiple checkpoints and altered expression of several cell cycle regulators in absence of DNA damage...
November 16, 2016: Scientific Reports
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