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https://www.readbyqxmd.com/read/28711844/application-of-kinetic-modeling-to-predict-the-fate-of-two-indoxacarb-metabolites-and-their-bound-residues-in-soil
#1
Minli Zhang, Sara A Whiting, Brett J Clark
Insecticide indoxacarb metabolites JT333 and MP819 were used as model compounds to assess the utilization of kinetic modeling to elucidate metabolic pathways, determine degradation kinetics of non-extractable residues (NER) and predict the accumulation potential of the released NER in soil. Soil adsorption coefficients and degradation product formation were determined in different soils in laboratory. Inverse kinetic modeling was applied to explore the dynamics of dissipation of parent (P), formation of extractable metabolites (MET), NER and CO2, and to identify their routes of degradation in soil...
July 13, 2017: Science of the Total Environment
https://www.readbyqxmd.com/read/28704967/variability-in-dna-repair-capacity-levels-among-molecular-breast-cancer-subtypes-triple-negative-breast-cancer-shows-lowest-repair
#2
Jaime Matta, Carmen Ortiz, Jarline Encarnación, Julie Dutil, Erick Suárez
Breast cancer (BC) is a heterogeneous disease which many studies have classified in at least four molecular subtypes: Luminal A, Luminal B, HER2-Enriched, and Basal-like (including triple-negative breast cancer, TNBC). These subtypes provide information to stratify patients for better prognostic predictions and treatment selection. Individuals vary in their sensitivities to carcinogens due to differences in their DNA repair capacity (DRC) levels. Although our previous case-control study established low DRC (in terms of NER pathway) as a BC risk factor, we aim to study this effect among the molecular subtypes...
July 12, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28704716/transcriptional-consequences-of-xpa-disruption-in-human-cell-lines
#3
Mandira Manandhar, Megan G Lowery, Karen S Boulware, Kevin H Lin, Yue Lu, Richard D Wood
Nucleotide excision repair (NER) in mammalian cells requires the xeroderma pigmentosum group A protein (XPA) as a core factor. Remarkably, XPA and other NER proteins have been detected by chromatin immunoprecipitation at some active promoters, and NER deficiency is reported to influence the activated transcription of selected genes. However, the global influence of XPA on transcription in human cells has not been determined. We analyzed the human transcriptome by RNA sequencing (RNA-Seq). We first confirmed that XPA is confined to the cell nucleus even in the absence of external DNA damage, in contrast to previous reports that XPA is normally resident in the cytoplasm and is imported following DNA damage...
June 29, 2017: DNA Repair
https://www.readbyqxmd.com/read/28686598/processing-closely-spaced-lesions-during-nucleotide-excision-repair-triggers-mutagenesis-in-e-coli
#4
Régine Janel-Bintz, Rita L Napolitano, Asako Isogawa, Shingo Fujii, Robert P Fuchs
It is generally assumed that most point mutations are fixed when damage containing template DNA undergoes replication, either right at the fork or behind the fork during gap filling. Here we provide genetic evidence for a pathway, dependent on Nucleotide Excision Repair, that induces mutations when processing closely spaced lesions. This pathway, referred to as Nucleotide Excision Repair-induced Mutagenesis (NERiM), exhibits several characteristics distinct from mutations that occur within the course of replication: i) following UV irradiation, NER-induced mutations are fixed much more rapidly (t ½ ≈ 30 min) than replication dependent mutations (t ½ ≈ 80-100 min) ii) NERiM specifically requires DNA Pol IV in addition to Pol V iii) NERiM exhibits a two-hit dose-response curve that suggests processing of closely spaced lesions...
July 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28654754/potential-strategies-to-target-protein-protein-interactions-in-the-dna-damage-response-and-repair-pathways
#5
Naoaki Fujii
This review article discusses some insights about generating novel mechanistic inhibitors of the DNA damage response and repair (DDR) pathways by focusing on protein-protein interactions (PPIs) of the key DDR components. General requirements for PPI strategies, such as selecting the target PPI site on the basis of its functionality, are discussed first. Next, on the basis of functional rationale and biochemical feasibility to identify a PPI inhibitor, 26 PPIs in DDR pathways (BER, MMR, NER, NHEJ, HR, TLS, and ICL repair) are specifically discussed for inhibitor discovery to benefit cancer therapies using a DNA-damaging agent...
July 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28649747/synthesis-structure-and-biological-evaluation-of-a-platinum-carbazole-conjugate
#6
Young Cheun, Myong-Chul Koag, Youssef W Naguib, Hala Ouzon-Shubeita, Zhengrong Cui, Danaya Pakotiprapha, Seongmin Lee
Cisplatin resistance is caused, in part, by the efficient removal of the helix-distorting cisplatin 1,2-intrastrand crosslinks by nucleotide excision repair (NER) machinery. To make a platinum-DNA adduct that causes less helical distortion than the cisplatin 1,2-intrastrand adduct, we designed and synthesized a monofunctional platinum-carbazole conjugate (carbazoleplatin). The 2.5Å crystal structure of carbazoleplatin-DNA adduct revealed both the monoplatination of the N7 of a guanine (G) base and the intercalation into two G:C base pairs while causing a minor distortion of the DNA helix...
June 26, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28552776/differential-sensitivities-of-cellular-xpa-and-parp-1-to-arsenite-inhibition-and-zinc-rescue
#7
Xiaofeng Ding, Xixi Zhou, Karen L Cooper, Juliana Huestis, Laurie G Hudson, Ke Jian Liu
Arsenite directly binds to the zinc finger domains of the DNA repair protein poly (ADP ribose) polymerase (PARP)-1, and inhibits PARP-1 activity in the base excision repair (BER) pathway. PARP inhibition by arsenite enhances ultraviolet radiation (UVR)-induced DNA damage in keratinocytes, and the increase in DNA damage is reduced by zinc supplementation. However, little is known about the effects of arsenite and zinc on the zinc finger nucleotide excision repair (NER) protein xeroderma pigmentosum group A (XPA)...
May 25, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28521214/def1-and-dst1-play-distinct-roles-in-repair-of-ap-lesions-in-highly-transcribed-genomic-regions
#8
Norah Owiti, Christopher Lopez, Shivani Singh, Andrei Stephenson, Nayun Kim
Abasic or AP sites generated by spontaneous DNA damage accumulate at a higher rate in actively transcribed regions of the genome in S. cerevisiae and are primarily repaired by base excision repair (BER) pathway. We have demonstrated that transcription-coupled nucleotide excision repair (NER) pathway can functionally replace BER to repair those AP sites located on the transcribed strand much like the strand specific repair of UV-induced pyrimidine dimers. Previous reports indicate that Rad26, a yeast homolog of transcription-repair coupling factor CSB, partly mediates strand-specific repair of UV-dimers as well as AP lesions...
May 10, 2017: DNA Repair
https://www.readbyqxmd.com/read/28484591/brothers-in-arms-emerging-roles-of-rna-epigenetics-in-dna-damage-repair
#9
Jinwei Zhang
N6-methyladenosine (m(6)A) is a widespread posttranscriptional RNA modification that occurs in tRNA, rRNA, snRNA, viral RNAs, and more recently is shown to occur in mRNA in a dynamic, reversible manner. At the epicenter of RNA epigenetics, m(6)A influences essentially all stages of RNA metabolism. As a result, m(6)A modulates cell differentiation and pluripotency, cell cycle and tumorigenesis, and several types of stress responses, etc. A recent report by Shi and colleagues uncovers a novel pathway in which m(6)A RNA, its associated enzymes, and DNA polymerase κ constitute an early-response system that confers cellular resistance to ultraviolet irradiation, separate from the canonical nucleotide excision repair (NER) pathway that normally repairs UV-induced DNA damage...
2017: Cell & Bioscience
https://www.readbyqxmd.com/read/28472716/combined-loss-of-three-dna-damage-response-pathways-renders-c-elegans-intolerant-to-light
#10
Ivo van Bostelen, Marcel Tijsterman
Infliction of DNA damage initiates a complex cellular reaction - the DNA damage response - that involves both signaling and DNA repair networks with many redundancies and parallel pathways. Here, we reveal the three strategies that the simple multicellular eukaryote, C. elegans, uses to deal with DNA damage induced by light. Separately inactivating repair or replicative bypass of photo-lesions results in cellular hypersensitivity towards UV-light, but impeding repair of replication associated DNA breaks does not...
April 14, 2017: DNA Repair
https://www.readbyqxmd.com/read/28460163/nucleotide-excision-repair-lesion-recognition-protein-rad4-captures-a-pre-flipped-partner-base-in-a-benzo-a-pyrene-derived-dna-lesion-how-structure-impacts-the-binding-pathway
#11
Hong Mu, Nicholas E Geacintov, Jung-Hyun Min, Yingkai Zhang, Suse Broyde
The xeroderma pigmentosum C protein complex (XPC) recognizes a variety of environmentally induced DNA lesions and is the key in initiating their repair by the nucleotide excision repair (NER) pathway. When bound to a lesion, XPC flips two nucleotide pairs that include the lesion out of the DNA duplex, yielding a productively bound complex that can lead to successful lesion excision. Interestingly, the efficiencies of NER vary greatly among different lesions, influencing their toxicity and mutagenicity in cells...
June 19, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28440919/rev7-the-regulatory-subunit-of-pol%C3%AE-undergoes-uv-induced-and-cul4-dependent-degradation
#12
Audesh Bhat, Zhoushuai Qin, Guifen Wang, Wangyang Chen, Wei Xiao
In eukaryotic cells, Rev7 interacts with Rev3 and functions as a regulatory subunit of Polζ, a translesion DNA synthesis (TLS) polymerase. In addition to its role in TLS, mammalian Rev7, also known as Mad2B/Mad2L2, participates in multiple cellular activities including cell cycle progression and double-strand break repair through its interaction with several proteins. Here we show that in mammalian cells, Rev7 undergoes ubiquitin/proteasome-mediated degradation upon UV irradiation in a time-dependent manner...
April 25, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28439991/melatonin-a-pleiotropic-molecule-that-modulates-dna-damage-response-and-repair-pathways
#13
REVIEW
Maryam Majidinia, Alireza Sadeghpour, Saeed Mehrzadi, Russel J Reiter, Nasrin Khatami, Bahman Yousefi
DNA repair is responsible for maintaining the integrity of the genome. Perturbations in the DNA repair pathways have been identified in several human cancers. Thus, compounds targeting DNA damage response (DDR) hold great promise in cancer therapy. A great deal of effort, in pursuit of new anticancer drugs, has been devoted to understanding the basic mechanisms and functions of the cellular DNA repair machinery. Melatonin, a widely produced indoleamine in all organisms, is associated with a reduced risk of cancer and has multiple regulatory roles on the different aspects of the DDR and DNA repair...
April 25, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28416769/nuclear-organization-of-nucleotide-excision-repair-is-mediated-by-ring1b-dependent-h2a-ubiquitylation
#14
Shalaka Chitale, Holger Richly
One of the major cellular DNA repair pathways is nucleotide excision repair (NER). It is the primary pathway for repair of various DNA lesions caused by exposure to ultraviolet (UV) light, such as cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts. Although lesion-containing DNA associates with the nuclear matrix after UV irradiation it is still not understood how nuclear organization affects NER. Analyzing unscheduled DNA synthesis (UDS) indicates that NER preferentially occurs in specific nuclear areas, viz the nucleolus...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28399901/activity-of-trabectedin-and-the-parp-inhibitor-rucaparib-in-soft-tissue-sarcomas
#15
Audrey Laroche, Vanessa Chaire, François Le Loarer, Marie-Paule Algéo, Christophe Rey, Kevin Tran, Carlo Lucchesi, Antoine Italiano
BACKGROUND: Trabectedin has recently been approved in the USA and in Europe for advanced soft-tissue sarcoma patients who have been treated with anthracycline-based chemotherapy without success. The mechanism of action of trabectedin depends on the status of both the nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways. Trabectedin results in DNA double-strand breaks. We hypothesized that PARP-1 inhibition is able to perpetuate trabectedin-induced DNA damage...
April 11, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28346378/dna-repair-pathway-alterations-in-bladder-cancer
#16
REVIEW
Kent W Mouw
Most bladder tumors have complex genomes characterized by a high mutation burden as well as frequent copy number alterations and chromosomal rearrangements. Alterations in DNA repair pathways-including the double-strand break (DSB) and nucleotide excision repair (NER) pathways-are present in bladder tumors and may contribute to genomic instability and drive the tumor phenotype. DNA damaging such as cisplatin, mitomycin C, and radiation are commonly used in the treatment of muscle-invasive or metastatic bladder cancer, and several recent studies have linked specific DNA repair pathway defects with sensitivity to DNA damaging-based therapy...
March 27, 2017: Cancers
https://www.readbyqxmd.com/read/28342452/contribution-of-genetic-factors-to-platinum-based-chemotherapy-sensitivity-and-prognosis-of-non-small-cell-lung-cancer
#17
REVIEW
Cristina Pérez-Ramírez, Marisa Cañadas-Garre, Miguel Ángel Molina, Ana I Robles, María José Faus-Dáder, Miguel Ángel Calleja-Hernández
Although platinum-based chemotherapy remains the standard treatment for advanced NSCLC patients, clinical outcomes are poor and most patients develop high-grade toxicities. Genetic factors, such as single nucleotide polymorphisms (SNPs) involved in platinum pharmacodynamics, metabolism and mechanism of action, may account for inter-individual differences shown in effectiveness and toxicity. Polymorphisms in genes involved in DNA repair and others such as PI3K/PTEN/AKT and TGF-β pathways have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with platinum-based chemotherapy...
January 2017: Mutation Research
https://www.readbyqxmd.com/read/28329680/major-roles-for-pyrimidine-dimers-nucleotide-excision-repair-and-atr-in-the-alternative-splicing-response-to-uv-irradiation
#18
Manuel J Muñoz, Nicolás Nieto Moreno, Luciana E Giono, Adrián E Cambindo Botto, Gwendal Dujardin, Giulia Bastianello, Stefania Lavore, Antonio Torres-Méndez, Carlos F M Menck, Benjamin J Blencowe, Manuel Irimia, Marco Foiani, Alberto R Kornblihtt
We have previously found that UV irradiation promotes RNA polymerase II (RNAPII) hyperphosphorylation and subsequent changes in alternative splicing (AS). We show now that UV-induced DNA damage is not only necessary but sufficient to trigger the AS response and that photolyase-mediated removal of the most abundant class of pyrimidine dimers (PDs) abrogates the global response to UV. We demonstrate that, in keratinocytes, RNAPII is the target, but not a sensor, of the signaling cascade initiated by PDs. The UV effect is enhanced by inhibition of gap-filling DNA synthesis, the last step in the nucleotide excision repair pathway (NER), and reduced by the absence of XPE, the main NER sensor of PDs...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28283089/e-coli-mismatch-repair-enhances-at-to-gc-mutagenesis-caused-by-alkylating-agents
#19
Kota Nakano, Yoko Yamada, Eizo Takahashi, Sakae Arimoto, Keinosuke Okamoto, Kazuo Negishi, Tomoe Negishi
Alkylating agents are known to induce the formation of O(6)-alkylguanine (O(6)-alkG) and O(4)-alkylthymine (O(4)-alkT) in DNA. These lesions have been widely investigated as major sources of mutations. We previously showed that mismatch repair (MMR) facilitates the suppression of GC-to-AT mutations caused by O(6)-methylguanine more efficiently than the suppression of GC-to-AT mutations caused by O(6)-ethylguanine. However, the manner by which O(4)-alkyT lesions are repaired remains unclear. In the present study, we investigated the repair pathway involved in the repair of O(4)-alkT...
March 2017: Mutation Research
https://www.readbyqxmd.com/read/28278049/mismatch-repair-proteins-recruited-to-ultraviolet-light-damaged-sites-lead-to-degradation-of-licensing-factor-cdt1-in-the-g1-phase
#20
Miyuki Tanaka, Michiyo Takahara, Kohei Nukina, Akiyo Hayashi, Wataru Sakai, Kaoru Sugasawa, Yasushi Shiomi, Hideo Nishitani
Cdt1 is rapidly degraded by CRL4(Cdt2) E3 ubiquitin ligase after UV (UV) irradiation. Previous reports revealed that the nucleotide excision repair (NER) pathway is responsible for the rapid Cdt1-proteolysis. Here, we show that mismatch repair (MMR) proteins are also involved in the degradation of Cdt1 after UV irradiation in the G1 phase. First, compared with the rapid (within ∼15 min) degradation of Cdt1 in normal fibroblasts, Cdt1 remained stable for ∼30 min in NER-deficient XP-A cells, but was degraded within ∼60 min...
April 3, 2017: Cell Cycle
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