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https://www.readbyqxmd.com/read/28336131/modulating-the-dna-damage-response-to-improve-treatment-response-in-cervical-cancer
#1
L H Cossar, A G Schache, J M Risk, J J Sacco, N J Jones, R Lord
Cervical cancer is the fourth most common cause of cancer-related death in women worldwide and new therapeutic approaches are needed to improve clinical outcomes for this group of patients. Current treatment protocols for locally advanced and metastatic disease consist of ionising radiation and chemotherapy. Chemoradiation induces cytotoxic levels of DNA double-strand breaks, which activates programmed cell death via the DNA damage response (DDR). Cervical cancers are unique given an almost exclusive association with human papillomavirus (HPV) infection; a potent manipulator of the DDR, with the potential to alter tumour sensitivity to DNA-damaging agents and influence treatment response...
March 20, 2017: Clinical Oncology: a Journal of the Royal College of Radiologists
https://www.readbyqxmd.com/read/28334174/dna-damage-response-in-hematopoietic-stem-cells-an-evolutionary-trade-off-between-blood-regeneration-and-leukemia-suppression
#2
Shahar Biechonski, Muhammad Yassin, Michael Milyavsky
Self-renewing and multipotent hematopoietic stem cells (HSCs) maintain lifelong hematopoiesis. Their enormous regenerative potential coupled with lifetime persistence in the body, in contrast with the Progenitors, demand tight control of HSCs genome stability. Indeed, failure to accurately repair DNA damage in HSCs is associated with bone marrow failure and accelerated leukemogenesis. Recent observations exposed remarkable differences in several DNA-damage response (DDR) aspects between HSCs and Progenitors, especially in their DNA-repair capacities and susceptibility to apoptosis...
March 15, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28325772/tet3-mediated-dna-oxidation-promotes-atr-dependent-dna-damage-response
#3
Dewei Jiang, Shu Wei, Fei Chen, Ying Zhang, Jiali Li
An efficient, accurate, and timely DNA damage response (DDR) is crucial for the maintenance of genome integrity. Here, we report that ten-eleven translocation dioxygenase (TET) 3-mediated conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in response to ATR-dependent DDR regulates DNA repair. ATR-dependent DDR leads to dynamic changes in 5hmC levels and TET3 enzymatic activity. We show that TET3 is an ATR kinase target that oxidizes DNA during ATR-dependent DNA damage repair. Modulation of TET3 expression and activity affects DNA damage signaling and DNA repair and consequently cell death...
March 21, 2017: EMBO Reports
https://www.readbyqxmd.com/read/28324505/probing-the-telomere-damage-response
#4
Rekha Rai, Sandy Chang
Telomere dysfunctions, rendered through replicative attrition of telomeric DNA or due to the removal of shelterin components, are recognized as DNA double-stranded breaks (DSBs) by the DNA damage repair (DDR) pathway. This leads to the activation of DNA damage checkpoint sensors, including the Mre11-Rad50-Nbs1 (MRN) complex, γ-H2AX and 53BP1, the ATM and ATR signal-transducing kinases, and downstream effectors, including Chk1, Chk2, and p53. Robust DNA damage response signals at dysfunctional telomeres, achieved by the complete deletion of TRF2 or by expressing dominant-negative mutant TPP1ΔRD, can be detected by their association with γ-H2AX and 53BP1 forming "telomere dysfunction induced foci (TIFs)...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28320880/rna-mediated-cis-regulation-in-acinetobacter-baumannii-modulates-stress-induced-phenotypic-variation
#5
Carly Ching, Kevin Gozzi, Björn Heinemann, Yunrong Chai, Veronica G Godoy
In the nosocomial opportunistic pathogen Acinetobacter baumannii, RecA-dependent mutagenesis, which causes antibiotic resistance acquisition, is linked to the DNA damage response (DDR). Notably, unlike the Escherichia coli paradigm, recA and DDR gene expression in A. baumannii are bimodal. Namely, there is phenotypic variation upon DNA damage, which may provide a bet-hedging strategy for survival. Thus, understanding recA gene regulation is key to elucidate the yet unknown DDR regulation in A. baumannii Here, we identify a structured 5' Untranslated Region (5' UTR) in the recA transcript which serves as a cis-regulatory element...
March 20, 2017: Journal of Bacteriology
https://www.readbyqxmd.com/read/28320735/the-retinoblastoma-homolog-rbr1-mediates-localization-of-the-repair-protein-rad51-to-dna-lesions-in-arabidopsis
#6
Sascha Biedermann, Hirofumi Harashima, Poyu Chen, Maren Heese, Daniel Bouyer, Kostika Sofroni, Arp Schnittger
The retinoblastoma protein (Rb), which typically functions as a transcriptional repressor of E2F-regulated genes, represents a major control hub of the cell cycle. Here, we show that loss of the Arabidopsis Rb homolog RETINOBLASTOMA-RELATED 1 (RBR1) leads to cell death, especially upon exposure to genotoxic drugs such as the environmental toxin aluminum. While cell death can be suppressed by reduced cell-proliferation rates, rbr1 mutant cells exhibit elevated levels of DNA lesions, indicating a direct role of RBR1 in the DNA-damage response (DDR)...
March 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28315153/effects-of-histone-deacetylase-inhibitory-prodrugs-on-epigenetic-changes-and-dna-damage-response-in-tumor-and-heart-of-glioblastoma-xenograft
#7
Nataly Tarasenko, Abraham Nudelman, Gabriela Rozic, Suzanne M Cutts, Ada Rephaeli
The histone deacetylase (HDAC) inhibitory prodrugs of butyric (AN7) and valproic (AN446) acids, which release the active acids upon metabolic degradation, were studied examining their differential effects on the viability, HDAC inhibitory activity and the DNA damage response (DDR), in glioblastoma cell and normal human astrocytes (NHAs). In xenografts of glioblastoma, AN7 or AN446 given or the combination of each of them with Dox augmented the anticancer activity of Dox and protected the heart from its toxicity...
March 17, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28302478/molecular-mechanisms-of-discrotophos-induced-toxicity-in-hepg2-cells-the-role-of-csa-in-oxidative-stress
#8
You-Cheng Hseu, Tung-Wei Hsu, Heng-Dao Lin, Chin Hui Chen, Ssu Ching Chen
Dicrotophos (Dic), an insecticide and acaricide, is used against a variety of sucking, boring and chewing pests. It was proven that Dic induced oxidative DNA damage in HepG2 cells. However, the molecular mechanisms of this compound were still unclear. First of all, the cytotoxicity and oxidative DNA damage were confirmed. Next, using RNA-seq for detecting differential expressed genes (DEGs) in cells treated with 50 μM Dic for 24 h, we showed that the dysregulation of these genes, irrespective of up (1298 genes) or down (2125 genes) regulation, could be attributed to some diverse pathways/metabolisms using KEGG analysis, particularly in DNA damage responses (DDRs) such as oxidative phosphorylation, nucleotide excision repair and cell cycle arrest...
March 14, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28301513/influence-of-a-pre-stimulation-with-chronic-low-dose-uvb-on-stress-response-mechanisms-in-human-skin-fibroblasts
#9
Marie-Catherine Drigeard Desgarnier, Frédéric Fournier, Arnaud Droit, Patrick J Rochette
Exposure to solar ultraviolet type B (UVB), through the induction of cyclobutane pyrimidine dimer (CPD), is the major risk factor for cutaneous cancer. Cells respond to UV-induced CPD by triggering the DNA damage response (DDR) responsible for signaling DNA repair, programmed cell death and cell cycle arrest. Underlying mechanisms implicated in the DDR have been extensively studied using single acute UVB irradiation. However, little is known concerning the consequences of chronic low-dose of UVB (CLUV) on the DDR...
2017: PloS One
https://www.readbyqxmd.com/read/28299394/caenorhabditis-elegans-as-a-powerful-alternative-model-organism-to-promote-research-in-genetic-toxicology-and-biomedicine
#10
REVIEW
Sebastian Honnen
In view of increased life expectancy the risk for disturbed integrity of genetic information increases. This inevitably holds the implication for higher incidence of age-related diseases leading to considerable cost increase in health care systems. To develop preventive strategies it is crucial to evaluate external and internal noxae as possible threats to our DNA. Especially the interplay of DNA damage response (DDR) and DNA repair (DR) mechanisms needs further deciphering. Moreover, there is a distinct need for alternative in vivo test systems for basic research and also risk assessment in toxicology...
March 15, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28289428/inflammation-dna-damage-helicobacter-pylori-and-gastric-tumorigenesis
#11
REVIEW
Polyxeni Kalisperati, Evangelia Spanou, Ioannis S Pateras, Penelope Korkolopoulou, Anastasia Varvarigou, Ioannis Karavokyros, Vassilis G Gorgoulis, Panayiotis G Vlachoyiannopoulos, Stavros Sougioultzis
Helicobacter pylori (H. pylori) is a Gram negative bacterium that colonizes the stomach of almost half human population. It has evolved to escape immune surveillance, establishes lifelong inflammation, predisposing to genomic instability and DNA damage, notably double strand breaks. The epithelial host cell responds by activation of DNA damage repair (DDR) machinery that seems to be compromised by the infection. It is therefore now accepted that genetic damage is a major mechanism operating in cases of H. pylori induced carcinogenesis...
2017: Frontiers in Genetics
https://www.readbyqxmd.com/read/28288624/cdk5-links-with-dna-damage-response-and-cancer
#12
REVIEW
Wan Liu, Jun Li, Yu-Shu Song, Yue Li, Yu-Hong Jia, Hai-Dong Zhao
As an atypical member of cyclin dependent kinase family, Cyclin dependent kinase 5 (Cdk5) is considered as a neuron-specific kinase in the past decade due to the abundant existence of its activator p35 in post-mitotic neurons. Recent studies show that Cdk5 participates in a series of biological and pathological processes in non-neuronal cells, and is generally dysregulated in various cancer cells. The inhibition or knockdown of Cdk5 has been proven to play an anti-cancer role through various mechanisms, and can synergize the killing effect of chemotherapeutics...
March 14, 2017: Molecular Cancer
https://www.readbyqxmd.com/read/28278048/brca1-recruitment-to-damaged-dna-sites-is-dependent-on-cdk9
#13
Thales C Nepomuceno, Vanessa C Fernandes, Thiago T Gomes, Renato S Carvalho, Guilherme Suarez-Kurtz, Alvaro N Monteiro, Marcelo A Carvalho
Double strand break lesions, the most toxic type of DNA damage, are repaired primarily through 2 distinct pathways: homology-directed recombination (HR) and non-homologous end-joining (NHEJ). BRCA1 and 53BP1, 2 proteins containing the BRCT modular domain, play an important role in DNA damage response (DDR) by orchestrating the decision between HR and NHEJ, but the precise mechanisms regarding both pathways are not entirely understood. Previously, our group identified a putative interaction between BRCA1 and BARD1 (BRCA1-associated RING domain 1) and the cyclin-dependent kinase (CDK9)...
February 22, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28271657/dna-damage-response-is-hijacked-by-human-papillomaviruses-to-complete-their-life-cycle
#14
Shi-Yuan Hong
The DNA damage response (DDR) is activated when DNA is altered by intrinsic or extrinsic agents. This pathway is a complex signaling network and plays important roles in genome stability, tumor transformation, and cell cycle regulation. Human papillomaviruses (HPVs) are the main etiological agents of cervical cancer. Cervical cancer ranks as the fourth most common cancer among women and the second most frequent cause of cancer-related death worldwide. Over 200 types of HPVs have been identified and about one third of these infect the genital tract...
2017: Journal of Zhejiang University. Science. B
https://www.readbyqxmd.com/read/28270508/discoidin-domain-receptor-2-mediates-collagen-induced-activation-of-membrane-type-1-matrix-metalloproteinase-in-human-fibroblasts
#15
Iwona Majkowska, Yasuyuki Shitomi, Noriko Ito, Nathanael S Gray, Yoshifumi Itoh
Membrane-Type 1 Matrix Metalloproteinase (MT1-MMP) is a membrane-bound MMP that is highly expressed in cells with invading capacity including fibroblasts and invasive cancer cell. A potential physiological stimulus for MT1-MMP expression is fibrillar collagen, and it has been shown that it upregulates both MT1-MMP gene and functions in various cell types. However, the mechanisms of collagen-mediated MT1-MMP activation is not clearly understood. In this study we identified discoidin domain receptor 2 (DDR2) as a crucial receptor that mediates this process in human fibroblasts...
March 7, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28270498/a-randomized-phase-ii-neoadjuvant-study-of-cisplatin-paclitaxel-with-or-without-everolimus-in-patients-with-stage-ii-iii-triple-negative-breast-cancer-tnbc
#16
Bojana Jovanovic, Ingrid A Mayer, Erica L Mayer, Vandana G Abramson, Aditya Bardia, Melinda Sanders, Maria G Kuba, Monica Valeria Estrada, J Scott Beeler, Timothy M Shaver, Kimberly N Johnson, Violeta Sanchez, Jennifer M Rosenbluth, Patrick M Dillon, Andres Forrero-Torres, Jenny C Chang, Ingrid Meszoely, Ana Grau, Brian D Lehmann, Yu Shyr, Quanhu Sheng, Sheau-Chiann Chen, Carlos L Arteaga, Jennifer A Pietenpol
PURPOSE: Due to inherent disease heterogeneity, targeted therapies have eluded TNBC, and biomarkers predictive of treatment response have not yet been identified. This study was designed to determine if the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic anti-tumor effects in TNBC. EXPERIMENTAL DESIGN: Stage II/III patients with TNBC were enrolled in a randomized phase II trial of preoperative weekly cisplatin, paclitaxel and daily everolimus or placebo for 12 weeks, until definitive surgery...
March 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28264028/parvovirus-b19-ns1-protein-induces-cell-cycle-arrest-at-g2-phase-by-activating-the-atr-cdc25c-cdk1-pathway
#17
Peng Xu, Zhe Zhou, Min Xiong, Wei Zou, Xuefeng Deng, Safder S Ganaie, Steve Kleiboeker, Jianxin Peng, Kaiyu Liu, Shengqi Wang, Shui Qing Ye, Jianming Qiu
Human parvovirus B19 (B19V) infection of primary human erythroid progenitor cells (EPCs) arrests infected cells at both late S-phase and G2-phase, which contain 4N DNA. B19V infection induces a DNA damage response (DDR) that facilitates viral DNA replication but is dispensable for cell cycle arrest at G2-phase; however, a putative C-terminal transactivation domain (TAD2) within NS1 is responsible for G2-phase arrest. To fully understand the mechanism underlying B19V NS1-induced G2-phase arrest, we established two doxycycline-inducible B19V-permissive UT7/Epo-S1 cell lines that express NS1 or NS1mTAD2, and examined the function of the TAD2 domain during G2-phase arrest...
March 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28263861/proximity-of-radiation-desiccation-response-motif-to-the-core-promoter-is-essential-for-basal-repression-as-well-as-gamma-radiation-induced-gyrb-gene-expression-in-deinococcus-radiodurans
#18
Narasimha Anaganti, Bhakti Basu, Rita Mukhopadhyaya, Shree Kumar Apte
The radioresistant D. radiodurans regulates its DNA damage regulon (DDR) through interaction between a 17bp palindromic cis-regulatory element called the Radiation Desiccation Response Motif (RDRM), the DdrO repressor and a protease IrrE. The role of RDRM in regulation of DDR was dissected by constructing RDRM sequence-, position- or deletion-variants of Deinococcal gyrB gene (DR0906) promoter and by RDRM insertion in the non-RDRM groESL gene (DR0606) promoter, and monitoring the effect of such modifications on the basal as well as gamma radiation inducible promoter activity by quantifying fluorescence of a GFP reporter...
March 2, 2017: Gene
https://www.readbyqxmd.com/read/28262819/rug3-and-atm-synergistically-regulate-the-alternative-splicing-of-mitochondrial-nad2-and-the-dna-damage-response-in-arabidopsis-thaliana
#19
Chao Su, Hongtao Zhao, Yankun Zhao, Hongtao Ji, Youning Wang, Liya Zhi, Xia Li
The root apical meristem (RAM) determines both RAM activity and the growth of roots. Plant roots are constantly exposed to adverse environmental stresses that can cause DNA damage or cell cycle arrest in the RAM; however, the mechanism linking root meristematic activity and RAM size to the DNA damage response (DDR) is unclear. Here, we demonstrate that a loss of function in RCC1/UVR8/GEF-Like 3 (RUG3) substantially augmented the DDR and produced a cell cycle arrest in the RAM in rug3 mutant, leading to root growth retardation...
March 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28260023/silencing-bmi1-radiosensitizes-human-breast-cancer-cells-by-inducing-dna-damage-and-autophagy
#20
James Griffith, Daniel Andrade, Meghna Mehta, William Berry, Doris M Benbrook, Natarajan Aravindan, Terence S Herman, Rajagopal Ramesh, Anupama Munshi
Overexpression of BMI1 in human cancer cells, a member of the polycomb group of repressive complexes, correlates with advanced stage of disease, aggressive clinico-pathological behavior, poor prognosis, and resistance to radiation and chemotherapy. Studies have shown that experimental reduction of BMI1 protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increased susceptibility to cytotoxic agents and radiation therapy. Although a role for BMI1 in cancer progression and its importance as a molecular target for cancer therapy has been established, information on the impact of silencing BMI1 in triple-negative breast cancer (TNBC) and its consequence on radiotherapy have not been well studied...
February 28, 2017: Oncology Reports
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