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https://www.readbyqxmd.com/read/29221109/protein-phosphatase-4-regulatory-subunit-2-ppp4r2-is-recurrently-deleted-in-acute-myeloid-leukemia-and-required-for-efficient-dna-double-strand-break-repair
#1
Julia K Herzig, Lars Bullinger, Alpaslan Tasdogan, Philipp Zimmermann, Martin Schlegel, Veronica Teleanu, Daniela Weber, Frank G Rücker, Peter Paschka, Anna Dolnik, Edith Schneider, Florian Kuchenbauer, Florian H Heidel, Christian Buske, Hartmut Döhner, Konstanze Döhner, Verena I Gaidzik
We have previously identified a recurrent deletion at chromosomal band 3p14.1-p13 in patients with acute myeloid leukemia (AML). Among eight protein-coding genes, this microdeletion affects the protein phosphatase 4 regulatory subunit 2 (PPP4R2), which plays an important role in DNA damage response (DDR). Investigation of mRNA expression during murine myelopoiesis determined that Ppp4r2 is higher expressed in more primitive hematopoietic cells. PPP4R2 expression in primary AML samples compared to healthy bone marrow was significantly lower, particularly in patients with 3p microdeletion or complex karyotype...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29207595/cdk1-promotes-nascent-dna-synthesis-and-induces-resistance-of-cancer-cells-to-dna-damaging-therapeutic-agents
#2
Hongwei Liao, Fang Ji, Xinwei Geng, Meichun Xing, Wen Li, Zhihua Chen, Huahao Shen, Songmin Ying
Cyclin dependent kinase 1 (CDK1) is essential for cell viability and plays a vital role in many biological events including cell cycle control, DNA damage repair, and checkpoint activation. Here, we identify an unanticipated role for CDK1 in promoting nascent DNA synthesis during S-phase. We report that a short duration of CDK1 inhibition, which does not perturb cell cycle progression, triggers a replication-associated DNA damage response (DDR). This DDR is associated with a disruption of replication fork progression and leads to genome instability...
October 31, 2017: Oncotarget
https://www.readbyqxmd.com/read/29206199/a-novel-receptor-tyrosine-kinase-switch-promotes-gastrointestinal-stromal-tumor-drug-resistance
#3
Sergei Boichuk, Aigul Galembikova, Pavel Dunaev, Elena Valeeva, Elena Shagimardanova, Oleg Gusev, Svetlana Khaiboullina
The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc...
December 5, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29200877/microtubule-targeting-agents-can-sensitize-cancer-cells-to-ionizing-radiation-by-an-interphase-based-mechanism
#4
Daniel Markowitz, Grace Ha, Rosamaria Ruggieri, Marc Symons
Background: The cytotoxic effects of microtubule-targeting agents (MTAs) are often attributed to targeted effects on mitotic cells. In clinical practice, MTAs are combined with DNA-damaging agents such as ionizing radiation (IR) with the rationale that mitotic cells are highly sensitive to DNA damage. In contrast, recent studies suggest that MTAs synergize with IR by interfering with the trafficking of DNA damage response (DDR) proteins during interphase. These studies, however, have yet to demonstrate the functional consequences of interfering with interphase microtubules in the presence of IR...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/29194355/characterization-of-the-ebv-induced-persistent-dna-damage-response
#5
Amy Y Hafez, Micah A Luftig
Epstein-Barr virus (EBV) is an oncogenic herpesvirus that is ubiquitous in the human population. Early after EBV infection in vitro, primary human B cells undergo a transient period of hyper-proliferation, which results in replicative stress and DNA damage, activation of the DNA damage response (DDR) pathway and, ultimately, senescence. In this study, we investigated DDR-mediated senescence in early arrested EBV-infected B cells and characterized the establishment of persistent DNA damage foci. We found that arrested EBV-infected B cells exhibited an increase in promyelocytic leukemia nuclear bodies (PML NBs), which predominantly localized to markers of DNA damage, as well as telomeric DNA...
December 1, 2017: Viruses
https://www.readbyqxmd.com/read/29186331/ddr-efficient-computational-method-to-predict-drug-target-interactions-using-graph-mining-and-machine-learning-approaches
#6
Rawan S Olayan, Haitham Ashoor, Vladimir B Bajic
Motivation: Finding computationally drug-target interactions (DTIs) is a convenient strategy to identify new DTIs at low cost with reasonable accuracy. However, the current DTI prediction methods suffer the high false positive prediction rate. Results: We developed DDR, a novel method that improves the DTI prediction accuracy. DDR is based on the use of a heterogeneous graph that contains known DTIs with multiple similarities between drugs and multiple similarities between target proteins...
November 24, 2017: Bioinformatics
https://www.readbyqxmd.com/read/29180822/damage-induced-lncrnas-control-the-dna-damage-response-through-interaction-with-ddrnas-at-individual-double-strand-breaks
#7
Flavia Michelini, Sethuramasundaram Pitchiaya, Valerio Vitelli, Sheetal Sharma, Ubaldo Gioia, Fabio Pessina, Matteo Cabrini, Yejun Wang, Ilaria Capozzo, Fabio Iannelli, Valentina Matti, Sofia Francia, G V Shivashankar, Nils G Walter, Fabrizio d'Adda di Fagagna
The DNA damage response (DDR) preserves genomic integrity. Small non-coding RNAs termed DDRNAs are generated at DNA double-strand breaks (DSBs) and are critical for DDR activation. Here we show that active DDRNAs specifically localize to their damaged homologous genomic sites in a transcription-dependent manner. Following DNA damage, RNA polymerase II (RNAPII) binds to the MRE11-RAD50-NBS1 complex, is recruited to DSBs and synthesizes damage-induced long non-coding RNAs (dilncRNAs) from and towards DNA ends...
November 27, 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/29180510/the-mrna-processing-factor-cstf-50-and-ubiquitin-escort-factor-p97-are-brca1-bard1-cofactors-involved-in-chromatin-remodeling-during-dna-damage-response
#8
Danae Fonseca, Jorge Baquero, Michael R Murphy, Gamage Aruggoda, Sophia Varriano, Carmen Sapienza, Oksana Mashadova, Shadaqur Rahman, Frida E Kleiman
The cellular response to DNA damage is an intricate mechanism that involves the interplay among several pathways. In this study, we provide evidence of the role of the polyadenylation factor CstF-50 and the ubiquitin (Ub)-escort factor p97 as cofactors of BRCA1/BARD1 E3 Ub ligase, facilitating chromatin remodeling during DNA damage response (DDR). CstF-50 and p97 formed (a) complex(es) with BRCA1/BARD1, Ub and some of BRCA1/BARD1 substrates, such as RNA polymerase II (RNAP II) and histones. Besides, CstF-50 and p97 had an additive effect on the activation of the ubiquitination of these BRCA1/BARD1 substrates during DDR...
November 27, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29179029/3ez-20ac-ingenol-induces-cell-specific-apoptosis-in-cyclin-d1-over-expression-through-the-activation-of-atr-and-downregulation-of-p-akt
#9
Shohei Miyata, Li-Yan Wang, Susumu Kitanaka
Acute lymphoblastic leukemia (ALL) samples exhibit an activated PI3K/Akt pathway, which suggests a general role of Akt in the development of leukemia. We have previously used western blot analysis to show that the catalytic topoisomerase (topo) inhibitor, 3EZ, 20Ac-ingenol, induced DNA damage response (DDR), which activated ATR, downregulated p-Akt through upregulation of PTEN level, and led to cell cycle arrest or apoptosis. In this study, we used ATR or PTEN siRNA and observed that the specific cell arrest and apoptosis of BALL-1 cells in DDR caused by 3EZ, 20Ac-ingenol was dependant on activation of ATR and downregulation of nuclear p-Akt through upregulation of PTEN...
August 24, 2017: Leukemia Research
https://www.readbyqxmd.com/read/29177481/cdyl1-fosters-double-strand-break-induced-transcription-silencing-and-promotes-homology-directed-repair
#10
Enas R Abu-Zhayia, Samah W Awwad, Bella Ben-Oz, Hanan Khoury-Haddad, Nabieh Ayoub
Cells have evolved DNA damage response (DDR) to repair DNA lesions and thus preserving genomic stability and impeding carcinogenesis. DNA damage induction is accompanied by transient transcription repression. Here, we describe a previously unrecognized role of chromodomain Y-like (CDYL1) protein in fortifying double-strand break (DSB)-induced transcription repression and repair. We showed that CDYL1 is rapidly recruited to damaged euchromatic regions in a poly [ADP-ribose] polymerase 1 (PARP1)-dependent, but ataxia telangiectasia mutated (ATM)-independent, manner...
November 21, 2017: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/29175474/enhanced-h3k4me3-modifications-are-involved-in-the-transactivation-of-dna-damage-responsive-genes-in-workers-exposed-to-low-level-benzene
#11
Jie Li, Xiumei Xing, Xinjie Zhang, Boxuan Liang, Zhini He, Chen Gao, Shan Wang, Fangping Wang, Haiyan Zhang, Shan Zeng, Junling Fan, Liping Chen, Zhengbao Zhang, Bo Zhang, Caixia Liu, Qing Wang, Weiwei Lin, Guanghui Dong, Huanwen Tang, Wen Chen, Yongmei Xiao, Daochuan Li
In this study, we explore whether altered global histone modifications respond to low-level benzene exposure as well as their association with the hematotoxicity. We recruited 147 low-level benzene-exposed workers and 122 control workers from a petrochemical factory in Maoming City, Guangdong Province, China. The internal exposure marker level, urinary S-phenylmercapturic acid (SPMA), in benzene-exposed workers was 1.81-fold higher than that of the controls (P < 0.001). ELISA method was established to examine the specific histone modifications in human peripheral blood lymphocytes (PBLCs) of workers...
November 22, 2017: Environmental Pollution
https://www.readbyqxmd.com/read/29173760/targeting-dna-damage-in-sclc
#12
REVIEW
Victoria Foy, Maximilian W Schenk, Katie Baker, Fabio Gomes, Alice Lallo, Kristopher K Frese, Martin Forster, Caroline Dive, Fiona Blackhall
SCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's. The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability...
December 2017: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
https://www.readbyqxmd.com/read/29170789/crebbp-and-p300-lysine-acetyl-transferases-in-the-dna-damage-response
#13
REVIEW
Ilaria Dutto, Claudia Scalera, Ennio Prosperi
The CREB-binding protein (CREBBP, or in short CBP) and p300 are lysine (K) acetyl transferases (KAT) belonging to the KAT3 family of proteins known to modify histones, as well as non-histone proteins, thereby regulating chromatin accessibility and transcription. Previous studies have indicated a tumor suppressor function for these enzymes. Recently, they have been found to acetylate key factors involved in DNA replication, and in different DNA repair processes, such as base excision repair, nucleotide excision repair, and non-homologous end joining...
November 23, 2017: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29167269/ring-finger-protein-126-rnf126-suppresses-ionizing-radiation-induced-p53-binding-protein-1-53bp1-foci-formation
#14
Nam Soo Lee, Hae Ryung Chang, Soomi Kim, Jae-Hoon Ji, Joorak Lee, Hyun Ji Lee, Yoojeong Seo, Misun Kang, Joo Seok Han, Kyungjae Myung, Yonghwan Kim, Hongtae Kim
Cells have evolved sophisticated mechanisms to maintain genomic integrity in response to DNA damage. Ionizing radiation (IR) induced DNA damage results in the formation of IR induced foci (iRIF) in the nucleus. The iRIF formation is part of the DNA damage response (DDR), which is an essential signaling cascade that must be strictly regulated because either the loss of or an augmented DDR leads to loss of genome integrity. Accordingly, negative regulation of the DDR is as critical as its activation. In this study, we have identified ring finger protein 126 (RNF126) as a negative regulator of the DDR from a screen of iRIF containing 53BP1...
November 22, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29163809/distinct-signaling-events-promote-resistance-to-mitoxantrone-and-etoposide-in-pediatric-aml-a-children-s-oncology-group-report
#15
Xin Long, Robert B Gerbing, Todd A Alonzo, Michele S Redell
Despite aggressive chemotherapy including mitoxantrone and etoposide, relapse occurs for almost half of children with acute myeloid leukemia (AML). Since both drugs inhibit topoisomerase II and cause DNA double strand breaks, resistance could be achieved by enhanced DNA damage repair (DDR), via homologous recombination (HR) and/or non-homologous end joining (NHEJ). An important source of extrinsic chemoresistance is the bone marrow stroma. We aimed to reveal intrinsic and stroma-induced signaling pathways that contribute to chemoresistance...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29163782/bmi1-reduces-atr-activation-and-signalling-caused-by-hydroxyurea
#16
Xiaozeng Lin, Fengxiang Wei, Peter Whyte, Damu Tang
BMI1 facilitates DNA damage response (DDR) induced by double strand DNA breaks; however, it remains unknown whether BMI1 functions in single strand DNA (ssDNA) lesions-initiated DDR. We report here that BMI1 reduces hydroxyurea-elicited ATR activation, thereby reducing the S-phase checkpoints. Hydroxyurea induces ssDNA lesions, which activate ATR through binding TOPBP1 as evidenced by phosphorylation of ATR at threonine 1989 (ATRpT1989). ATR subsequently phosphorylates H2AX at serine 139 (γH2AX) and CHK1 at serine 345 (CHK1pS345), leading to phosphorylation of CDK1 at tyrosine 15 (CDK1pY15) and S-phase arrest...
October 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/29161272/global-transcriptome-profile-reveals-abundance-of-dna-damage-response-and-repair-genes-in-individuals-from-high-level-natural-radiation-areas-of-kerala-coast
#17
Vinay Jain, Birajalaxmi Das
The high level natural radiation areas (HLNRA) of Kerala coast in south west India is unique for its wide variation in the background radiation dose (<1.0mGy to 45mGy/year) and vast population size. Several biological studies conducted in this area did not reveal any adverse effects of chronic low dose and low dose rate radiation on human population. In the present study, global transcriptome analysis was carried out in peripheral blood mono-nuclear cells of 36 individuals belonging to different background dose groups [NLNRA, (Group I, ≤1...
2017: PloS One
https://www.readbyqxmd.com/read/29144413/epstein-barr-virus-hijacks-dna-damage-response-transducers-to-orchestrate-its-life-cycle
#18
REVIEW
Pok Man Hau, Sai Wah Tsao
The Epstein-Barr virus (EBV) is a ubiquitous virus that infects most of the human population. EBV infection is associated with multiple human cancers, including Burkitt's lymphoma, Hodgkin's lymphoma, a subset of gastric carcinomas, and almost all undifferentiated non-keratinizing nasopharyngeal carcinoma. Intensive research has shown that EBV triggers a DNA damage response (DDR) during primary infection and lytic reactivation. The EBV-encoded viral proteins have been implicated in deregulating the DDR signaling pathways...
November 16, 2017: Viruses
https://www.readbyqxmd.com/read/29144403/the-non-homologous-end-joining-protein-paxx-acts-to-restrict-hsv-1-infection
#19
Ben J Trigg, Katharina B Lauer, Paula Fernandes Dos Santos, Heather Coleman, Gabriel Balmus, Daniel S Mansur, Brian J Ferguson
Herpes simplex virus 1 (HSV-1) has extensive interactions with the host DNA damage response (DDR) machinery that can be either detrimental or beneficial to the virus. Proteins in the homologous recombination pathway are known to be required for efficient replication of the viral genome, while different members of the classical non-homologous end-joining (c-NHEJ) pathway have opposing effects on HSV-1 infection. Here, we have investigated the role of the recently-discovered c-NHEJ component, PAXX (Paralogue of XRCC4 and XLF), which we found to be excluded from the nucleus during HSV-1 infection...
November 16, 2017: Viruses
https://www.readbyqxmd.com/read/29141944/dna-damage-responses-and-p53-in-the-aging-process
#20
Hui-Ling Ou, Björn Schumacher
The genome is constantly attacked by genotoxic insults. DNA damage has long been established to cause cancer development through its mutagenic consequences. Conversely, DNA damage is induced during radiation- and chemotherapy to drive cells into apoptosis or senescence as outcomes of the DNA damage response (DDR). More recently, DNA damage has been recognized as a causal factor for the aging process. The causal role of DNA damage in aging and age-related diseases is illustrated by numerous congenital progeroid syndromes that are caused by mutations in genome maintenance pathways...
November 15, 2017: Blood
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