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nucleotide excision repair

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https://www.readbyqxmd.com/read/28934497/systematic-analysis-of-dna-crosslink-repair-pathways-during-development-and-aging-in-caenorhabditis-elegans
#1
David M Wilson, Matthias Rieckher, Ashley B Williams, Björn Schumacher
DNA interstrand crosslinks (ICLs) are generated by endogenous sources and chemotherapeutics, and pose a threat to genome stability and cell survival. Using Caenorhabditis elegans mutants, we identify DNA repair factors that protect against the genotoxicity of ICLs generated by trioxsalen/ultraviolet A (TMP/UVA) during development and aging. Mutations in nucleotide excision repair (NER) components (e.g. XPA-1 and XPF-1) imparted extreme sensitivity to TMP/UVA relative to wild-type animals, manifested as developmental arrest, defects in adult tissue morphology and functionality, and shortened lifespan...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28933851/design-and-structure-guided-development-of-novel-inhibitors-of-the-xeroderma-pigmentosum-group-a-xpa-protein-dna-interaction
#2
Navnath S Gavande, Pamela VanderVere-Carozza, Akaash K Mishra, Tyler L Vernon, Katherine S Pawelczak, John J Turchi
XPA is a unique and essential protein required for the nucleotide excision DNA repair pathway and represents a therapeutic target in oncology. Herein, we are the first to develop novel inhibitors of the XPA-DNA interaction through structure-guided drug design efforts. Ester derivatives of the compounds 1 (X80), 22, and 24 displayed excellent inhibitory activity (IC50 of 0.82 ± 0.18 μM and 1.3 ± 0.22 μM, respectively) but poor solubility. We have synthesized novel amide derivatives that retain potency and have much improved solubility...
September 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28927196/the-intricate-interplay-between-msi-and-polymorphisms-of-dna-repair-enzymes-in-gastric-cancer-h-pylori-associated
#3
Isabelle Joyce de Lima Silva-Fernandes, Emanuele Silva de Oliveira, Juliana Carvalho Santos, Marcelo Lima Ribeiro, Adriana Camargo Ferrasi, Maria Inês de Moura Campos Pardini, Rommel Mário Rodriguez Burbano, Silvia Helena Barem Rabenhorst
Gastric cancer is the fourth most common type of cancer worldwide. Helicobacter pylori is a well-established risk factor and may cause injuries to genomic integrity through an inefficient DNA repair. This study aimed to examine the influence of polymorphisms in DNA repair enzymes using markers for microsatellite instability (MSI). Polymorphisms of DNA repair enzymes were detected by PCR-RFLP and MSI, by high resolution melt (HRM) analysis. Helicobacter pylori detection and genotyping were accomplished by PCR...
July 1, 2017: Mutagenesis
https://www.readbyqxmd.com/read/28924235/single-nucleotide-polymorphisms-of-nucleotide-excision-repair-pathway-are-significantly-associated-with-outcomes-of-platinum-based-chemotherapy-in-lung-cancer
#4
Xiao Song, Shiming Wang, Xuan Hong, Xiaoying Li, Xueying Zhao, Cong Huai, Hongyan Chen, Zhiqiang Gao, Ji Qian, Jiucun Wang, Baohui Han, Chunxue Bai, Qiang Li, Junjie Wu, Daru Lu
Nucleotide excision repair (NER) pathway plays critical roles in repairing DNA disorders caused by platinum. To comprehensively understand the association between variants of NER and clinical outcomes of platinum-based chemotherapy, 173 SNPs in 27 genes were selected to evaluate association with toxicities and efficiency in 1004 patients with advanced non-small cell lung cancer. The results showed that consecutive significant signals were observed in XPA, RPA1, POLD1, POLD3. Further subgroup analysis showed that GTF2H4 presented consecutive significant signals in clinical benefit among adenocarcimoma...
September 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28923949/cytosine-deamination-and-base-excision-repair-cause-r-loop-induced-cag-repeat-fragility-and-instability-in-saccharomyces-cerevisiae
#5
Xiaofeng A Su, Catherine H Freudenreich
CAG/CTG repeats are structure-forming repetitive DNA sequences, and expansion beyond a threshold of ∼35 CAG repeats is the cause of several human diseases. Expanded CAG repeats are prone to breakage, and repair of the breaks can cause repeat contractions and expansions. In this study, we found that cotranscriptional R-loops formed at a CAG-70 repeat inserted into a yeast chromosome. R-loops were further elevated upon deletion of yeast RNaseH genes and caused repeat fragility. A significant increase in CAG repeat contractions was also observed, consistent with previous human cell studies...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28916651/escherichia-coli-and-neisseria-gonorrhoeae-uvrd-helicase-unwinds-g4-dna-structures
#6
Kaustubh Shukla, Roshan Thakur, Debayan Ganguli, Desirazu Rao, Ganesh Nagaraju
G-quadruplex (G4) secondary structures have been implicated in various biological processes including gene expression, DNA replication and telomere maintenance. However, unresolved G4 structures impede replication progression which can lead to generation of DNA double-strand breaks and genome instability. Helicases have been shown to resolve G4 structures to facilitate faithful duplication of the genome. Escherichia coli UvrD (EcUvrD) helicase plays a crucial role in nucleotide excision repair, mismatch repair and in the regulation of homologous recombination...
September 15, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28912372/genome-wide-maps-of-alkylation-damage-repair-and-mutagenesis-in-yeast-reveal-mechanisms-of-mutational-heterogeneity
#7
Peng Mao, Alexander J Brown, Ewa P Malc, Piotr A Mieczkowski, Michael J Smerdon, Steven A Roberts, John J Wyrick
DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome-depleted regions, and slower repair and higher mutation density within strongly positioned nucleosomes...
September 14, 2017: Genome Research
https://www.readbyqxmd.com/read/28903417/disruption-of-dna-repair-in-cancer-cells-by-ubiquitination-of-a-destabilising-dimerization-domain-of-nucleotide-excision-repair-protein-ercc1
#8
Lanlan Yang, Ann-Marie Ritchie, David W Melton
DNA repair pathways present in all cells serve to preserve genome stability, but in cancer cells they also act reduce the efficacy of chemotherapy. The endonuclease ERCC1-XPF has an important role in the repair of DNA damage caused by a variety of chemotherapeutic agents and there has been intense interest in the use of ERCC1 as a predictive marker of therapeutic response in non-small cell lung carcinoma, squamous cell carcinoma and ovarian cancer. We have previously validated ERCC1 as a therapeutic target in melanoma, but all small molecule ERCC1-XPF inhibitors reported to date have lacked sufficient potency and specificity for clinical use...
August 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28902838/the-cryo-electron-microscopy-structure-of-human-transcription-factor-iih
#9
Basil J Greber, Thi Hoang Duong Nguyen, Jie Fang, Pavel V Afonine, Paul D Adams, Eva Nogales
Human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair. The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation...
September 21, 2017: Nature
https://www.readbyqxmd.com/read/28893909/processive-searching-ability-varies-among-members-of-the-gap-filling-dna-polymerase-x-family
#10
Michael J Howard, Samuel H Wilson
DNA repair proteins must locate rare damaged sites within the genome. DNA polymerase beta (Pol β), a member of the DNA polymerase X family that is involved in base excision repair, uses a processive hopping search mechanism to locate substrates. This effectively enhances its search footprint on DNA, increasing the probability of locating damaged sites. Processive searching has been reported or proposed for many DNA-binding proteins, raising the question of how widespread or specific to certain enzymes the ability to perform this function is...
September 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28893156/erythrosine-b-and-quinoline-yellow-dyes-regulate-dna-repair-gene-expression-in-human-hepg2-cells
#11
Farah Md Chequer, Vinicius P Venancio, Mara R Almeida, Alexandre F Aissa, Maria Lourdes P Bianchi, Lusânia Mg Antunes
Erythrosine B (ErB) is a cherry pink food colorant and is widely used in foods, drugs, and cosmetics. Quinoline yellow (QY) is a chinophthalon derivative used in cosmetic compositions for application to the skin, lips, and/or body surface. Previously, ErB and QY synthetic dyes were found to induce DNA damage in HepG2 cells. The aim of this study was to investigate the molecular basis underlying the genotoxicity attributed to ErB and QY using the RT(2) Profiler polymerase chain reaction array and by analyzing the expression profile of 84 genes involved in cell cycle arrest, apoptosis, and DNA repair in HepG2 cells...
January 1, 2017: Toxicology and Industrial Health
https://www.readbyqxmd.com/read/28878296/genetic-variants-in-ercc1-and-xpc-predict-survival-outcome-of-non-small-cell-lung-cancer-patients-treated-with-platinum-based-therapy
#12
Ruoxin Zhang, Ming Jia, Huijing Xue, Yuan Xu, Mengyun Wang, Meiling Zhu, Menghong Sun, Jianhua Chang, Qingyi Wei
Nucleotide excision repair (NER) plays a vital role in platinum-induced DNA damage during chemotherapy. We hypothesize that regulatory single nucleotide polymorphisms (rSNPs) of the core NER genes modulate clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy (PBS). We investigated associations of 25 rSNPs in eight NER genes with progression free survival (PFS) and overall survival (OS) in 710 NSCLC patients. We found that ERCC1 rs3212924 AG/GG and XPC rs2229090 GC/CC genotypes were associated with patients' PFS (HRadj = 1...
September 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28860187/analysis-of-dna-binding-by-human-factor-xeroderma-pigmentosum-complementation-group-a-xpa-provides-insight-into-its-interactions-with-nucleotide-excision-repair-substrates
#13
Norie Sugitani, Markus W Voehler, Michelle S Roh, Agnieszka M Topolska-Woś, Walter J Chazin
Xeroderma pigmentosum (XP) complementation group A (XPA) is an essential scaffolding protein in the multi-protein nucleotide excision repair (NER) machinery. The interaction of XPA with DNA is a core function of this protein; a number of mutations in the DNA binding domain (DBD) are associated with XP disease. Although structures of the central globular domain of human XPA and data on binding of DNA substrates have been reported, the structural basis for XPAs DNA binding activity remains unknown. X-ray crystal structures of the central globular domain of yeast XPA (Rad14) with lesion-containing DNA duplexes have provided valuable insights, but the DNA substrates used for this study do not correspond to the substrates of XPA as it functions within the NER machinery...
August 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28857155/prevalent-somatic-brca1-mutations-shape-clinically-relevant-genomic-patterns-of-nasopharyngeal-carcinoma-in-southeast-europe
#14
George Fountzilas, Amanda Psyrri, Eleni Giannoulatou, Ioannis Tikas, Kyriaki Manousou, Dimitra Rontogianni, Elisabeta Ciuleanu, Tudor Ciuleanu, Liliana Resiga, Thomas Zaramboukas, Kyriaki Papadopoulou, Mattheos Bobos, Sofia Chrisafi, Eleftheria Tsolaki, Konstantinos Markou, Evangelos Giotakis, Angelos Koutras, Elsa Psoma, Anna Kalogera-Fountzila, Maria Skondra, Christina Bamia, Dimitrios Pectasides, Vassiliki Kotoula
Genomic patterns of nasopharyngeal carcinomas (NPC) have as yet been studied in Southeast Asian (SEA) patients. Here, we investigated genomic patterns of locally advanced NPC Southeast European (SEE) patients treated with chemo-radiotherapy. We examined 126 tumors (89% EBV positive) from Greek and Romanian NPC patients with massively parallel sequencing. Paired tumor-cell-rich (TC) and infiltrating-lymphocyte-rich (TILs) samples were available in 19, and paired tumor - germline samples in 68 cases. Top mutated genes were BRCA1 (54% of all tumors); BRCA2 (29%); TP53 (22%); KRAS (18%)...
August 31, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28854356/multilayered-reprogramming-in-response-to-persistent-dna-damage-in-c-%C3%A2-elegans
#15
Diletta Edifizi, Hendrik Nolte, Vipin Babu, Laia Castells-Roca, Michael M Mueller, Susanne Brodesser, Marcus Krüger, Björn Schumacher
DNA damage causally contributes to aging and age-related diseases. Mutations in nucleotide excision repair (NER) genes cause highly complex congenital syndromes characterized by growth retardation, cancer susceptibility, and accelerated aging in humans. Orthologous mutations in Caenorhabditis elegans lead to growth delay, genome instability, and accelerated functional decline, thus allowing investigation of the consequences of persistent DNA damage during development and aging in a simple metazoan model. Here, we conducted proteome, lipidome, and phosphoproteome analysis of NER-deficient animals in response to UV treatment to gain comprehensive insights into the full range of physiological adaptations to unrepaired DNA damage...
August 29, 2017: Cell Reports
https://www.readbyqxmd.com/read/28854355/uv-induced-rpa1-acetylation-promotes-nucleotide-excision-repair
#16
Hanqing He, Jiajia Wang, Ting Liu
Replication protein A (RPA) is a multifunctional, single-stranded DNA-binding protein complex and plays a critical role in DNA replication and damage response. Herein, we show that the 70-kDa subunit of RPA (RPA1) is acetylated on lysine 163 by the acetyltransferases GCN5 and PCAF and that such acetylation is reversed principally via the action of the deacetylase HDAC6. UV irradiation promotes cytoplasmic translocation of HDAC6, thereby disrupting the interaction of HDAC6 with RPA1 and increasing RPA1 acetylation...
August 29, 2017: Cell Reports
https://www.readbyqxmd.com/read/28854354/pcaf-gcn5-mediated-acetylation-of-rpa1-promotes-nucleotide-excision-repair
#17
Meimei Zhao, Rui Geng, Xiang Guo, Ruoshi Yuan, Xiao Zhou, Yanyan Zhong, Yanfei Huo, Mei Zhou, Qinjian Shen, Yinglu Li, Weiguo Zhu, Jiadong Wang
The RPA complex can integrate multiple stress signals into diverse responses by activating distinct DNA repair pathways. However, it remains unclear how RPA1 elects to activate a specific repair pathway during different types of DNA damage. Here, we report that PCAF/GCN5-mediated K163 acetylation of RPA1 is crucial for nucleotide excision repair (NER) but is dispensable for other DNA repair pathways. Mechanistically, we demonstrate that the acetylation of RPA1 is critical for the steady accumulation of XPA at damaged DNA sites and preferentially activates the NER pathway...
August 29, 2017: Cell Reports
https://www.readbyqxmd.com/read/28854353/feeling-stressed-under-the-sun-rpa1-acetylation-to-the-rescue
#18
Debabrata Chakravarti, Tapas K Hazra
Nucleotide excision repair (NER) requires replication protein A (RPA), among others, to respond to DNA damaging agents. In this issue of Cell Reports, He et al. (2017) and Zhao et al. (2017) show acetylation of RPA1 regulates the UV-induced DNA damage response.
August 29, 2017: Cell Reports
https://www.readbyqxmd.com/read/28840550/nucleotide-excision-repair-from-neurodegeneration-to-cancer
#19
Anastasios Liakos, Matthieu D Lavigne, Maria Fousteri
DNA damage poses a constant threat to genome integrity taking a variety of shapes and arising by normal cellular metabolism or environmental insults. Human syndromes, characterized by increased cancer pre-disposition or early onset of age-related pathology and developmental abnormalities, often result from defective DNA damage responses and compromised genome integrity. Over the last decades intensive research worldwide has made important contributions to our understanding of the molecular mechanisms underlying genomic instability and has substantiated the importance of DNA repair in cancer prevention in the general population...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28835905/in-vitro-assay-to-measure-dna-polymerase-%C3%AE-nucleotide-insertion-coupled-with-the-dna-ligation-reaction-during-base-excision-repair
#20
Melike Çağlayan, Samuel H Wilson
We previously reported that oxidized nucleotide insertion by DNA polymerase β (pol β) can confound the DNA ligation step during base excision repair (BER) (Çağlayan et al., 2017). Here, we describe a method to investigate pol β nucleotide insertion coupled with DNA ligation, in the same reaction mixture including dGTP or 8-oxo-dGTP, pol β and DNA ligase l. This in vitro assay enables us to measure the products for correct vs. oxidized nucleotide insertion, DNA ligation, and ligation failure, i.e., abortive ligation products, as a function of reaction time...
June 20, 2017: Bio-protocol
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