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https://www.readbyqxmd.com/read/29030356/cell-cycle-and-dna-damage-response-pathway-is-involved-in-leptomeningeal-metastasis-of-non-small-cell-lung-cancer
#1
Yun Fan, Xuehua Zhu, Yan Xu, Xuesong Lu, Yanjun Xu, Mengzhao Wang, Haiyan Xu, Jingyan Ding, Xin Ye, Luo Fang, Zhiyu Huang, Lei Gong, Hongyang Lu, Weimin Mao, Min Hu
PURPOSE: Leptomeningeal metastases (LM) is a detrimental complication of non-small cell lung cancer (NSCLC) and associated with poor prognosis. However, the underlying mechanisms of the metastasis process are still poorly understood. EXPERIMENTAL DESIGN: We performed next-generation panel sequencing of primary tumor tissue, cerebrospinal fluid (CSF) and matched normal controls from epidermal growth factor receptor (EGFR) mutation-positive NSCLC patients with LM...
October 13, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29029401/lysine-methylation-of-fen1-by-set7-is-essential-for-its-cellular-response-to-replicative-stress
#2
Palaniraja Thandapani, Anthony M Couturier, Zhenbao Yu, Xing Li, Jean-François Couture, Shawn Li, Jean-Yves Masson, Stéphane Richard
The DNA damage response (DDR) is central to the cell survival and it requires post-translational modifications, in part, to sense the damage, amplify the signaling response and recruit and regulate DNA repair enzymes. Lysine methylation of histones such as H4K20 and non-histone proteins including p53 has been shown to be essential for the mounting of the DDR. It is well-known that the lysine methyltransferase SET7 regulates the DDR, as cells lacking this enzyme are hypersensitive to chemotherapeutic drugs. To define addition substrates of SET7 involved in the DDR, we screened a peptide array encompassing potential lysine methylation sites from >100 key DDR proteins and identified peptides from 58 proteins to be lysine methylated defining a methylation consensus sequence of [S>K(-2); S>R(-1); K(0)] consistent with previous findings...
September 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29026069/id3-regulates-the-mdc1-mediated-dna-damage-response-in-order-to-maintain-genome-stability
#3
Jung-Hee Lee, Seon-Joo Park, Gurusamy Hariharasudhan, Min-Ji Kim, Sung Mi Jung, Seo-Yeon Jeong, In-Youb Chang, Cheolhee Kim, Eunae Kim, Jihyeon Yu, Sangsu Bae, Ho Jin You
MDC1 plays a critical role in the DNA damage response (DDR) by interacting directly with several factors including γ-H2AX. However, the mechanism by which MDC1 is recruited to damaged sites remains elusive. Here, we show that MDC1 interacts with a helix-loop-helix (HLH)-containing protein called inhibitor of DNA-binding 3 (ID3). In response to double-strand breaks (DSBs) in the genome, ATM phosphorylates ID3 at serine 65 within the HLH motif, and this modification allows a direct interaction with MDC1. Moreover, depletion of ID3 results in impaired formation of ionizing radiation (IR)-induced MDC1 foci, suppression of γ-H2AX-bound MDC1, impaired DSB repair, cellular hypersensitivity to IR, and genomic instability...
October 12, 2017: Nature Communications
https://www.readbyqxmd.com/read/29025359/brca1-or-cdk12-loss-sensitizes-cells-to-chk1-inhibitors
#4
Hana Paculová, Juraj Kramara, Šárka Šimečková, Radek Fedr, Karel Souček, Ondřej Hylse, Kamil Paruch, Marek Svoboda, Martin Mistrík, Jiří Kohoutek
A broad spectrum of tumors develop resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly(ADP-ribose) polymerase 1/2 proteins and DNA damage response genes, including BRCA1, a factor involved in homologous recombination-mediated DNA repair, and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. CHK1 inhibitors have been shown to enhance the anti-cancer effect of DNA-damaging compounds...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/29021613/uncoupling-oncogene-induced-senescence-ois-and-dna-damage-response-ddr-triggered-by-dna-hyper-replication-lessons-from-primary-mouse-embryo-astrocytes-mea
#5
Marcos Seoane, José A Costoya, Víctor M Arce
Oncogene-induced senescence (OIS) is a complex process, in which activation of oncogenic signals during early tumorigenesis results in a high degree of DNA replication stress. The ensuing response to the DNA damage produces a permanent G1 arrest that prevents unlimited cell proliferation and lessens the development of tumours. However, despite the role of OIS in the proliferative arrest resulting from an activating oncogenic-lesion has obtained wide support, there is also evidence indicating that cells may overcome oncogene-induced senescence under some circumstances...
October 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29018079/setd2-alterations-impair-dna-damage-recognition-and-lead-to-resistance-to-chemotherapy-in-leukemia
#6
Brenton G Mar, S Haihua Chu, Josephine D Kahn, Andrei V Krivstov, Richard Koche, Cecilia A Castellano, Jacob L Kotlier, Rebecca L Zon, Marie E McConkey, Jonathan Chabon, Ryan Chappell, Peter V Grauman, James J Hsieh, Scott A Armstrong, Benjamin L Ebert
Mutations in SETD2, encoding the histone 3 lysine 36 trimethyltransferase, are enriched in relapsed acute lymphoblastic leukemia and MLL rearranged acute leukemia. We investigated the impact of SETD2 mutations on chemotherapy sensitivity in isogenic leukemia cell lines and in murine leukemia generated from a conditional knockout of Setd2SETD2 mutations led to resistance to DNA-damaging agents, cytarabine, 6-thioguanine, doxorubicin, and etoposide, but not to a non-DNA damaging agent, L-asparaginase. H3K36me3 localizes components of the DNA damage response pathway and SETD2 mutation impaired the DNA damage response (DDR), blunting apoptosis induced by cytotoxic chemotherapy...
October 10, 2017: Blood
https://www.readbyqxmd.com/read/28993289/sirt1-and-parp1-as-epigenome-safeguards-and-micrornas-as-sasp-associated-signals-in-cellular-senescence-and-aging
#7
REVIEW
Seyedhossein Hekmatimoghaddam, Ali Dehghani Firoozabadi, Mohamad Reza Zare-Khormizi, Fatemeh Pourrajab
Cellular senescence (CS) is underlying mechanism of organism aging and is closely interconnected with age-related diseases (ARDs). Thus, any attempt that influences CS, may be undertaken to reverse or inhibit senescence, whereby could prolong healthy life span. Until now, two main proposes are epigenetic and genetic modifications of cell fate. The first one concerns rejuvenation through effective reprogramming in cells undergoing senescence, or derived from very old or progeroid patients, by which is effective in vitro in induced pluripotent stem cells (iPSCs)...
October 6, 2017: Ageing Research Reviews
https://www.readbyqxmd.com/read/28986560/the-telomere-binding-protein-pot1-maintains-haematopoietic-stem-cell-activity-with-age
#8
Kentaro Hosokawa, Ben D MacArthur, Yoshiko Matsumoto Ikushima, Hirofumi Toyama, Yoshikazu Masuhiro, Shigemasa Hanazawa, Toshio Suda, Fumio Arai
Repeated cell divisions and aging impair stem cell function. However, the mechanisms by which this occurs are not fully understood. Here we show that protection of telomeres 1A (Pot1a), a component of the Shelterin complex that protects telomeres, improves haematopoietic stem cell (HSC) activity during aging. Pot1a is highly expressed in young HSCs, but declines with age. In mouse HSCs, Pot1a knockdown increases DNA damage response (DDR) and inhibits self-renewal. Conversely, Pot1a overexpression or treatment with POT1a protein prevents DDR, maintained self-renewal activity and rejuvenated aged HSCs upon ex vivo culture...
October 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28984489/directing-the-use-of-ddr-kinase-inhibitors-in-cancer-treatment
#9
Inger Brandsma, Emmy D G Fleuren, Chris T Williamson, Christopher J Lord
Introduction Defects in the DNA damage response (DDR) drive the development of cancer by fostering DNA mutation but also provide cancer-specific vulnerabilities that can be exploited therapeutically. The recent approval of three different PARP inhibitors for the treatment of ovarian cancer provides the impetus for further developing targeted inhibitors of many of the kinases involved in the DDR, including inhibitors of ATR, ATM, CHEK1, CHEK2, DNAPK and WEE1. Areas covered We summarise the current stage of development of these novel DDR kinase inhibitors, and describe which predictive biomarkers might be exploited to direct their clinical use...
October 6, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28978225/dual-role-of-nitric-oxide-in-regulating-the-response-of-%C3%AE-cells-to-dna-damage
#10
Bryndon J Oleson, John A Corbett
SIGNIFICANCE: Cytokines released in and around pancreatic islets during islet inflammation are believed to contribute to impaired β-cell function and β-cell death during the development of diabetes. Nitric oxide, produced by β-cells in response to cytokine exposure, controls many of the responses of β-cells during islet inflammation. Recent Advances. Although nitric oxide has been shown to inhibit insulin secretion and oxidative metabolism and induce DNA damage in β-cells, it also activates protective pathways that promote recovery of insulin secretion and oxidative metabolism and repair of damaged DNA...
October 5, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/28972393/aryl-hydrocarbon-receptor-suppresses-the-prostate-cancer-lncap-cell-growth-and-invasion-by-promoting-dna-damage-response-under-oxidative-stress
#11
Jing-Song Yu, Peng-Fei Leng, Yi-Fu Li, Yong-Quan Wang, Yan Wang, Rui-Hua An, Ji-Ping Qi
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that interacts with multiple signaling pathways during prostate development. In the present study, LNCaP cells were knocked down of AhR by siRNA, or treated with the AhR agonist 3-methylcholanthrene (3MC). The effects of AhR on LNCaP cells and the associated mechanisms were studied both under normal condition and under hydrogen peroxide (H2O2)-induced oxidative stress. MTT, transwell chamber assays and flow cytometry were employed to investigate cell proliferation, invasion, and apoptosis, respectively, whereas the DNA damage response (DDR) signaling (phosphorylation of ataxia-telangiectasia mutated [ATM], check-point kinase 2 [Chk2], histone H2AX, p53, and cleaved poly-ADP-ribose polymerase [PARP]) was detected by western blotting...
October 3, 2017: DNA and Cell Biology
https://www.readbyqxmd.com/read/28969091/cellular-senescence-senescence-associated-secretory-phenotype-and-chronic-kidney-disease
#12
REVIEW
Wen-Juan Wang, Guang-Yan Cai, Xiang-Mei Chen
Chronic kidney disease (CKD) is increasingly being accepted as a type of renal ageing. The kidney undergoes age-related alterations in both structure and function. To date, a comprehensive analysis of cellular senescence and senescence-associated secretory phenotype (SASP) in CKD is lacking. Hence, this review mainly discusses the relationship between the two phenomena to show the striking similarities between SASP and CKD-associated secretory phenotype (CASP). It has been reported that replicative senescence, stress-induced premature ageing, and epigenetic abnormalities participate in the occurrence and development of CKD...
September 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28963924/efficient-repair-of-dna-double-strand-breaks-in-individuals-from-high-level-natural-radiation-areas-of-kerala-coast-south-west-india
#13
Vinay Jain, Divyalakshmi Saini, P R Vivek Kumar, G Jaikrishan, Birajalaxmi Das
High level natural radiation areas (HLNRA) of Kerala coastal strip (55km long and 0.5km wide) in southwest India exhibit wide variations in the level of background dose (< 1.0-45.0mGy/year) due to thorium deposits in the beach sand. The areas with ≤1.5mGy/year are considered as normal level natural radiation area (NLNRA), whereas areas with >1.5mGy/year are HLNRA. Individuals belonging to HLNRA were stratified into two groups, Low dose group (LDG: 1.51-5.0mGy/year) and high dose group (HDG: >5.0mGy/year)...
September 20, 2017: Mutation Research
https://www.readbyqxmd.com/read/28954241/targeting-the-cohesive-cluster-phenotype-in-chordoma-via-%C3%AE-1-integrin-increases-ionizing-radiation-efficacy
#14
William L Harryman, Jaime M C Gard, Kelvin W Pond, Skyler J Simpson, Lucas H Heppner, Daniel Hernandez-Cortes, Andrew S Little, Jennifer M Eschbacher, Anne E Cress
Chordoma is a rare, radiation-resistant, skull-base and spinal tumor with high local recurrence containing mixed cell-adhesion phenotypes. We characterized DNA damage response (DDR) signaling (γH2AX, pKAP1, pATM) and survival response to ionizing radiation (IR) in human chordoma samples (42 resections, 23 patients) to test if blocking cell adhesion sensitizes U-CH1 tumor cells to IR. U-CH1 cells expressed brachyury, YAP, and laminin adhesion receptors (CD49c, CD49f, CD44), and approximately 15% to 20% of U-CH1 cells featured an α6 integrin-dependent (CD49f) cohesive cluster phenotype, which confers therapeutic resistance and aids metastasis...
September 24, 2017: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/28950914/resveratrol-inhibits-extranodal-nk-t-cell-lymphoma-through-activation-of-dna-damage-response-pathway
#15
Xianxian Sui, Canjing Zhang, Jianan Zhou, Shengxuan Cao, Chen Xu, Feng Tang, Xiuling Zhi, Bobin Chen, Songmei Wang, Lianhua Yin
BACKGROUND: Extranodal NK/T cell lymphoma (NKTCL) is a highly aggressive non-Hodgkin lymphoma with poor prognosis. Resveratrol (RSV, 3,5,4'-trihydroxystilbene), a natural nontoxic phenolic compound found in the skin of grapes and some other spermatophytes, performs multiple bioactivities, such as antioxidant activity, anti-aging activity, reduction of cardiovascular disease risk and anticarcinogenic effect. Here we report the anti-tumor effect of RSV in NKTCL cell lines SNT-8, SNK-10 and SNT-16...
September 26, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/28937603/proteome-stability-as-a-key-factor-of-genome-integrity
#16
REVIEW
Sentiljana Gumeni, Zoi Evangelakou, Vassilis G Gorgoulis, Ioannis P Trougakos
DNA damage is constantly produced by both endogenous and exogenous factors; DNA lesions then trigger the so-called DNA damaged response (DDR). This is a highly synchronized pathway that involves recognition, signaling and repair of the damage. Failure to eliminate DNA lesions is associated with genome instability, a driving force in tumorigenesis. Proteins carry out the vast majority of cellular functions and thus proteome quality control (PQC) is critical for the maintenance of cellular functionality. PQC is assured by the proteostasis network (PN), which under conditions of proteome instability address the triage decision of protein fold, hold, or degrade...
September 22, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28935440/effects-of-acute-restraint-and-unpredictable-chronic-mild-stress-on-brain-corticotrophin-releasing-factor-mrna-in-the-elevated-t-maze
#17
José S de Andrade, Isabel C Céspedes, Renata O Abrão, Joelcimar M da Silva, Ricardo Ceneviva, Daniel Araki Ribeiro, Jackson C Bittencourt, Milena B Viana
Corticotrophin releasing factor (CRF) modulates stress/anxiety-related responses. Previous studies showed that exposure to acute restraint and unpredictable chronic mild stress (UCMS) facilitates elevated T-maze (ETM) avoidance responses, an anxiogenic-like effect. This study verified the role of CRF in the modulation of ETM avoidance and escape reactions, in unstressed rats and in animals exposed to acute restraint or to UCMS, by quantifying CRF mRNA concentrations in stress/anxiety-related brain regions, through semiquantitative in situ hybridization...
September 19, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/28934154/why-human-papillomaviruses-activate-the-dna-damage-response-ddr-and-how-cellular-and-viral-replication-persists-in-the-presence-of-ddr-signaling
#18
REVIEW
Molly L Bristol, Dipon Das, Iain M Morgan
Human papillomaviruses (HPV) require the activation of the DNA damage response (DDR) in order to undergo a successful life cycle. This activation presents a challenge for the virus and the infected cell: how does viral and host replication proceed in the presence of a DDR that ordinarily arrests replication; and how do HPV16 infected cells retain the ability to proliferate in the presence of a DDR that ordinarily arrests the cell cycle? This raises a further question: why do HPV activate the DDR? The answers to these questions are only partially understood; a full understanding could identify novel therapeutic strategies to target HPV cancers...
September 21, 2017: Viruses
https://www.readbyqxmd.com/read/28930563/mass-spectrometry-based-proteomic-analysis-of-the-dna-damage-response
#19
Matthew P Stokes, Yiying Zhu, Charles L Farnsworth
In response to DNA damage, cells have evolved mechanisms to halt cell cycle progression, activate repair, or initiate apoptosis. These DNA damage response (DDR) pathways are critical for cellular survival in response to genomic insult, and play important roles in growth, development, and disease. Historically, mediators of DNA damage response signaling have been studied one or a few proteins at a time. Advances in mass spectrometry instrumentation and enrichment methods now allow for more global analysis of the DDR in cells and tissues...
January 1, 2018: Frontiers in Bioscience (Landmark Edition)
https://www.readbyqxmd.com/read/28919734/usefulness-of-the-desaturation-distance-ratio-from-the-six-minute-walk-test-for-patients-with-copd
#20
Yukari Fujimoto, Yutaro Oki, Masahiro Kaneko, Hideki Sakai, Shogo Misu, Takumi Yamaguchi, Yuji Mitani, Hisafumi Yasuda, Akira Ishikawa
PURPOSE: A straightforward, noninvasive method is needed to assess emphysema and pulmonary hypertension (PH) in COPD patients. The desaturation-distance ratio (DDR) is an index derived from the distance traveled and level of desaturation during a six-minute walk test (6MWT); it has previously been shown to be associated with percentage of forced expiratory volume in the first second of expiration (%FEV1.0) and percentage of diffusion capacity of the lung for carbon monoxide (%DLCO). The aim of this study was to examine the associations between DDR and emphysema and PH...
2017: International Journal of Chronic Obstructive Pulmonary Disease
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