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DNA glycosylases

Teresa Morales-Ruiz, Álvaro C Romero-Valenzuela, Vanessa M Vázquez-Grande, Teresa Roldán-Arjona, Rafael R Ariza, Dolores Córdoba-Cañero
Base excision repair (BER) is a major defense pathway against spontaneous DNA damage. This multistep process is initiated by DNA glycosylases that recognise and excise the damaged base, and proceeds by the concerted action of additional proteins that perform incision of the abasic site, gap filling and ligation. BER has been extensively studied in bacteria, yeasts and animals. Although knowledge of this pathway in land plants is increasing, there are no reports detecting BER in algae. We describe here an experimental in vitro system allowing the specific analysis of BER in the model alga Chlamydomonas reinhardtii...
March 5, 2018: DNA Repair
Tomoki Maegawa, Yuki Miyasaka, Misato Kobayashi, Naru Babaya, Hiroshi Ikegami, Fumihiko Horio, Masahide Takahashi, Tamio Ohno
Streptozotocin (STZ) has been widely used to induce diabetes in rodents. Strain-dependent variation in susceptibility to STZ has been reported; however, the gene(s) responsible for STZ susceptibility has not been identified. Here, we utilized the A/J-11SM consomic strain and a set of chromosome 11 (Chr. 11) congenic strains developed from A/J-11SM to identify a candidate STZ-induced diabetes susceptibility gene. The A/J strain exhibited significantly higher susceptibility to STZ-induced diabetes than the A/J-11SM strain, confirming the existence of a susceptibility locus on Chr...
March 9, 2018: Mammalian Genome: Official Journal of the International Mammalian Genome Society
Nidhi Sharma, Srinivas Chakravarthy, Matthew J Longley, William C Copeland, Aishwarya Prakash
The 16.5 kb mitochondrial genome is subjected to damage from reactive oxygen species (ROS) generated in the cell during normal cellular metabolism and external sources such as ionizing radiation and ultraviolet light. ROS cause harmful damage to DNA bases that could result in mutagenesis and various diseases, if not properly repaired. The base excision repair (BER) pathway is the primary pathway involved in maintaining the integrity of mtDNA. Several enzymes that partake in BER within the nucleus have also been identified in the mitochondria...
March 6, 2018: DNA Repair
Kristin L Limpose, Kelly S Trego, Zhentian Li, Sara W Leung, Altaf H Sarker, Jason A Shah, Suresh S Ramalingam, Erica M Werner, William S Dynan, Priscilla K Cooper, Anita H Corbett, Paul W Doetsch
Base excision repair (BER), which is initiated by DNA N-glycosylase proteins, is the frontline for repairing potentially mutagenic DNA base damage. The NTHL1 glycosylase, which excises DNA base damage caused by reactive oxygen species, is thought to be a tumor suppressor. However, in addition to NTHL1 loss-of-function mutations, our analysis of cancer genomic datasets reveals that NTHL1 frequently undergoes amplification or upregulation in some cancers. Whether NTHL1 overexpression could contribute to cancer phenotypes has not yet been explored...
March 7, 2018: Nucleic Acids Research
Katarzyna Mokra, Katarzyna Woźniak, Bożena Bukowska, Paulina Sicińska, Jaromir Michałowicz
Because bisphenol A (BPA) and some of its analogs have been supposed to influence development of cancer, we have assessed the effect of BPA, bisphenol S (BPS), bisphenol F (BPF) and bisphenol AF (BPAF) on DNA bases oxidation, which is a key process in cancer initiation. The analysis was conducted on human peripheral blood mononuclear cells (PBMCs), which are very useful model to assess genotoxic potential of various toxicants in different cell types. In order to determine oxidative damage to DNA pyrimidines and purines, alkaline version of the comet assay with DNA glycosylases, i...
February 27, 2018: Chemosphere
Juan Song, Fei Yin, Xia Li, Na Dong, Yingjie Zhu, Yanan Shao, Baoli Chen, Wei Jiang, Chen-Zhong Li
We developed a novel approach to determine formamidopyrimidine DNA glycosylase (FPG) activity by taking advantage of target-induced self-primed rolling circle amplification (RCA) and magnetic nanoprobes. Herein, a unique nick (8-oxoguanine, 8-oxoG) was positioned in duplex DNA containing P-circle and P1 , which together serve as a FPG substrate, RCA template, and RCA primer probe. The presence of FPG specifically binds 8-oxoG and cleaves the P-circle into two parts, producing 5'-phosphoryl termini. A phosphodiester bond between the 5'-phosphoryl and 3'-hydroxyl termini was formed with the addition of T4 DNA ligase, producing an unnicked circular strand...
March 8, 2018: Analyst
Blerta Green, Alberto Martin, Antoaneta Belcheva
C-Myc overexpression mediates lymphomagenesis, however, secondary genetic lesions are required for its full oncogenic potential. The origin and the mechanism of formation of these mutations are unclear. Using the lacI-mutation detection system, we show that secondary mutations occur early in B-cell development and are repaired by Msh2. The mutations at the lacI gene were predominantly at C:G base pairs and CpG motifs suggesting that they were formed due to cytosine deamination or oxidative damage of G. Hence, we investigated the role of Ogg1 and UNG glycosylases in c-Myc driven lymphomagenesis but found that their deficiencies did not influence the disease outcome in the Eµ c-Myc mouse model...
February 26, 2018: Experimental Hematology
Olga A Kladova, Milena Bazlekowa-Karaban, Sonia Baconnais, Olivier Piétrement, Alexander A Ishchenko, Bakhyt T Matkarimov, Danila A Iakovlev, Andrey Vasenko, Olga S Fedorova, Eric Le Cam, Barbara Tudek, Nikita A Kuznetsov, Murat Saparbaev
The base excision repair (BER) pathway consists of sequential action of DNA glycosylase and apurinic/apyrimidinic (AP) endonuclease necessary to remove a damaged base and generate a single-strand break in duplex DNA. Human multifunctional AP endonuclease 1 (APE1, a.k.a. APEX1, HAP-1, or Ref-1) plays essential roles in BER by acting downstream of DNA glycosylases to incise a DNA duplex at AP sites and remove 3'-blocking sugar moieties at DNA strand breaks. Human 8-oxoguanine-DNA glycosylase (OGG1), methyl-CpG-binding domain 4 (MBD4, a...
February 11, 2018: DNA Repair
Thais Ceresér Vilela, Pauline Souza Effting, Giulia Dos Santos Pedroso, Hemelin Farias, Lara Paganini, Helen Sorato Rebelo, Renata Tiescoski Nesi, Vanessa Moraes de Andrade, Ricardo Aurino de Pinho
Skeletal muscle aging is associated with loss of mass, function, and strength-a condition known as sarcopenia. It has been reported that sarcopenia can be attenuated by physical exercise. Therefore, we investigated whether 2 different physical exercise protocols could modulate and induce changes in oxidative and inflammatory parameters, as well as in BDNF and DNA repair enzyme levels in skeletal muscle tissue of aged rats. Aging Wistar rats performed treadmill or strength training for 50 min 3 to 4 times a week for 8 weeks...
February 19, 2018: Experimental Gerontology
Jamie E DeNizio, Emily K Schutsky, Kiara N Berrios, Monica Yun Liu, Rahul M Kohli
The introduction of site-specific DNA modifications to the genome or epigenome presents great opportunities for manipulating biological systems. Such changes are now possible through the combination of DNA-modifying enzymes with targeting modules, including dCas9, that can localize the enzymes to specific sites. In this review, we take a DNA modifying enzyme-centric view of recent advances. We highlight the variety of natural DNA-modifying enzymes-including DNA methyltransferases, oxygenases, deaminases, and glycosylases-that can be used for targeted editing and discuss how insights into the structure and function of these enzymes has further expanded editing potential by introducing enzyme variants with altered activities or by improving spatiotemporal control of modifications...
February 13, 2018: Current Opinion in Chemical Biology
Akula Deepa, Kodipelli Naveena, Roy Anindya
Iron deprivation induces transcription of genes required for iron uptake and transcription factor Aft1 and Aft2 mediate this by regulating transcriptional program in S. cerevisiae. Iron-dependent Fe(II) and 2-oxoglutarate-dependent dioxygenase family proteins are involved in various cellular pathways including DNA alkylation damage repair. Whether Aft1/Aft2 are required for DNA alkylation repair is currently unknown. In this report, we have analyzed DNA alkylation repair under iron-deprived condition. S. cerevisiae Tpa1 is a member of Fe(II) and 2-oxoglutarate-dependent dioxygenase family and we show that deletion of AFT1 and AFT2 genes affects Tpa1 function resulting in sensitivity to alkylating agent MMS...
February 9, 2018: FEMS Yeast Research
Orapan Manajit, Siwaporn Longyant, Paisarn Sithigorngul, Parin Chaivisuthangkura
Pseudomonas aeruginosa (P. aeruginosa) is an important opportunistic pathogen that causes serious infections in humans, including keratitis in contact lens wearers. Therefore, establishing a rapid, specific and sensitive method for the identification of P. aeruginosa is imperative. In the present study, the uracil-DNA-glycosylase-supplemented loop-mediated isothermal amplification combined with nanogold labeled hybridization probe (UDG-LAMP-AuNP) was developed for the detection of P. aeruginosa. UDG-LAMP was performed to prevent carry over contamination and the LAMP reactions can be readily observed using the nanogold probe...
February 2, 2018: Molecular Medicine Reports
Kohei Nukina, Akiyo Hayashi, Yasushi Shiomi, Kaoru Sugasawa, Motoaki Ohtsubo, Hideo Nishitani
CRL4Cdt2 ubiquitin ligase plays an important role maintaining genome integrity during the cell cycle. A recent report suggested that Cdk1 negatively regulates CRL4Cdt2 activity through phosphorylation of its receptor, Cdt2, but the involvement of phosphorylation remains unclear. To address this, we mutated all CDK consensus phosphorylation sites located in the C-terminal half region of Cdt2 (Cdt2-18A) and examined the effect on substrate degradation. We show that both cyclinA/Cdk2 and cyclinB/Cdk1 phosphorylated Cdt2 in vitro and that phosphorylation was reduced by the 18A mutation both in vitro and in vivo...
February 9, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Satomi Banno, Keiji Nishida, Takayuki Arazoe, Hitoshi Mitsunobu, Akihiko Kondo
In eukaryotes, the CRISPR-Cas9 system has now been widely used as a revolutionary genome engineering tool1, 2. However, in prokaryotes, the use of nuclease-mediated genome editing tools has been limited to negative selection for the already modified cells because of its lethality3, 4. Here, we report on deaminase-mediated targeted nucleotide editing (Target-AID) 5 adopted in Escherichia coli. Cytidine deaminase PmCDA1 fused to the nuclease-deficient CRISPR-Cas9 system achieved specific point mutagenesis at the target sites in E...
February 5, 2018: Nature Microbiology
Carlos Benítez-Buelga, Juan Miguel Baquero, Tereza Vaclova, Victoria Fernández, Paloma Martín, Lucia Inglada-Perez, Miguel Urioste, Ana Osorio, Javier Benítez
In this report, we have tried to gain molecular insight into a single nucleotide polymorphism (SNP) in the NEIL2 gene previously identified as "cancer risk modifier" for BRCA2 mutation carriers. To that end, we studied the role of this SNP (rs804271) on NEIL2 transcriptional regulation, oxidative DNA damage and genome instability in two independent set of samples: The first one was a series of eighty-six BRCA1 and BRCA2 mutation carriers and eighty non-carrier controls in which we evaluated the effect of the SNP on NEIL2 gene expression and oxidative DNA damage accumulation...
December 29, 2017: Oncotarget
Bart Kolendowski, Haider Hassan, Milica Krstic, Majdina Isovic, Gobi Thillainadesan, Ann F Chambers, Alan B Tuck, Joseph Torchia
BACKGROUND: The estrogen receptor (ER) is a ligand-dependant transcription factor expressed in many breast cancers and is the target of many endocrine-based cancer therapies. Genome-wide studies have shown that the ER binds to gene-specific enhancer regions in response to β-estradiol (E2) which undergo transcription producing noncoding enhancer RNA (eRNA). While eRNAs are important for transcriptional activation of neighboring genes, the mechanism remains poorly understood. RESULTS: Using ChIP-Seq we generate a global profile of thymine DNA glycosylase (TDG), an ER coactivator that plays an essential role in DNA demethylation, in response to E2 in the MCF7 breast cancer cell line...
January 29, 2018: Epigenetics & Chromatin
Yu-Ki Tahara, Douglas Auld, Debin Ji, Andrew A Beharry, Anna M Kietrys, David L Wilson, Marta Jimenez, Daniel King, Zachary Nguyen, Eric T Kool
The activity of DNA repair enzyme OGG1, which excises oxidized base 8-oxoguanine (8-OG) from DNA, is closely linked to mutagenesis, genotoxicity, cancer, and inflammation. To test the roles of OGG1-mediated repair in these pathways, we have undertaken the development of noncovalent small-molecule inhibitors of the enzyme. Screening of a PubChem-annotated library using a recently developed fluorogenic 8-oxoguanine excision assay resulted in multiple validated hit structures, including selected lead hit tetrahydroquinoline 1 (IC50 = 1...
January 27, 2018: Journal of the American Chemical Society
J Volk, C Ziemann, G Leyhausen, W Geurtsen
OBJECTIVES: Camphorquinone (CQ) is the most important photoinitiator used in dental composite resins. Sparse data indicate a mutagenic potential of CQ. Therefore, it was aim of this study to evaluate the cytotoxicity, genotoxicity, and mutagenicity of CQ in L5178Y TK+/- mouse lymphoma cells. METHODS: L5178Y/TK+/- cells were exposed to different concentrations of non-irradiated CQ (0.25-2.5mM). Cytotoxicity was evaluated by propidium iodide assay, determination of suspension growth rate, relative total growth and the mitotic index...
January 17, 2018: Dental Materials: Official Publication of the Academy of Dental Materials
Shirzad Fallahi, Seyedeh Fatemeh Moosavi, Azadeh Karimi, Ali Sharafi Chegeni, Mohammad Saki, Parsa Namdari, Mohammad Menati Rashno, Ali Mohamad Varzi, Mohammad Javad Tarrahi, Mohammad Almasian
The rapid and accurate detection of Cryptosporidium spp. is critically important for the prevention and timely treatment of cryptosporidiosis in AIDS patients (APs). This study was conducted to examine a UDG-LAMP technique for the first time to diagnose cryptosporidiosis in APs. After collecting demographic and clinical data, three stool samples were collected from the participants (120 volunteering APs). The microscopic examination of stained smears using the acid-fast method and the UDG-LAMP assay were performed for each sample...
December 24, 2017: Diagnostic Microbiology and Infectious Disease
Jizhen Shang, Zhi Li, Liping Liu, Dongmei Xi, Hua Wang
Human 8-oxoguanine DNA glycosylase (hOGG1) plays a significant role in maintaining the genomic integrity of living organisms for its capability of repairing DNA lesions. Accurate detection of hOGG1 activity would greatly facilitate the screening and early diagnosis of diseases. In this work, we report a nanopore-based sensing strategy to probe the hOGG1 activity by employing the enzyme-catalytic cleavage reaction of DNA substrate. The hOGG1 specifically catalyzed the removal of the 8-hydroxyguanine (8-oxoG) and cleaved the DNA substrates immobilized on magnetic beads, thereby releasing the output DNA which would quantitatively produce the signature current events when subjected to α-hemolysin (α-HL) nanopore test...
January 24, 2018: ACS Sensors
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