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BER pathway

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https://www.readbyqxmd.com/read/28521214/def1-and-dst1-play-distinct-roles-in-repair-of-ap-lesions-in-highly-transcribed-genomic-regions
#1
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/28490746/pathogenic-p62-sqstm1-mutations-impair-energy-metabolism-through-limitation-of-mitochondrial-substrates
#2
Fernando Bartolome, Noemi Esteras, Angeles Martin-Requero, Claire Boutoleau-Bretonniere, Martine Vercelletto, Audrey Gabelle, Isabelle Le Ber, Tadashi Honda, Albena T Dinkova-Kostova, John Hardy, Eva Carro, Andrey Y Abramov
Abnormal mitochondrial function has been found in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Mutations in the p62 gene (also known as SQSTM1) which encodes the p62 protein have been reported in both disorders supporting the idea of an ALS/FTD continuum. In this work the role of p62 in energy metabolism was studied in fibroblasts from FTD patients carrying two independent pathogenic mutations in the p62 gene, and in a p62-knock-down (p62 KD) human dopaminergic neuroblastoma cell line (SH-SY5Y)...
May 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28485930/reactivity-and-cross-linking-of-5-terminal-abasic-sites-within-dna
#3
Suzanne J Admiraal, Patrick J O'Brien
Nicking of the DNA strand immediately upstream of an internal abasic (AP) site produces 5'-terminal abasic (dRp) DNA. Both the intact and the nicked abasic species are reactive intermediates along the DNA base excision repair (BER) pathway and can be derailed by side reactions. Aberrant accumulation of the 5'-terminal abasic intermediate has been proposed to lead to cell death, so we explored its reactivity and compared it to the reactivity of the better-characterized internal abasic intermediate. We find that the 5'-terminal abasic group cross-links with the exocyclic amine of a nucleotide on the opposing strand to form an interstrand DNA-DNA cross-link (ICL)...
May 9, 2017: Chemical Research in Toxicology
https://www.readbyqxmd.com/read/28476660/%C3%AE-adrenergic-induced-sr-ca-2-leak-is-mediated-by-an-epac-nos-pathway
#4
Laëtitia Pereira, Dan J Bare, Samuel Galice, Thomas R Shannon, Donald M Bers
Cardiac β-adrenergic receptors (β-AR) and Ca(2+)-Calmodulin dependent protein kinase (CaMKII) regulate both physiological and pathophysiological Ca(2+) signaling. Elevated diastolic Ca(2+) leak from the sarcoplasmic reticulum (SR) contributes to contractile dysfunction in heart failure and to arrhythmogenesis. β-AR activation is known to increase SR Ca(2+) leak via CaMKII-dependent phosphorylation of the ryanodine receptor. Two independent and reportedly parallel pathways have been implicated in this β-AR-CaMKII cascade, one involving exchange protein directly activated by cAMP (Epac2) and another involving nitric oxide synthase 1 (NOS1)...
May 2, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/28466855/a-domain-in-human-exog-converts-apoptotic-endonuclease-to-dna-repair-exonuclease
#5
Michal R Szymanski, Wangsheng Yu, Aleksandra M Gmyrek, Mark A White, Ian J Molineux, J Ching Lee, Y Whitney Yin
Human EXOG (hEXOG) is a 5'-exonuclease that is crucial for mitochondrial DNA repair; the enzyme belongs to a nonspecific nuclease family that includes the apoptotic endonuclease EndoG. Here we report biochemical and structural studies of hEXOG, including structures in its apo form and in a complex with DNA at 1.81 and 1.85 Å resolution, respectively. A Wing domain, absent in other ββα-Me members, suppresses endonuclease activity, but confers on hEXOG a strong 5'-dsDNA exonuclease activity that precisely excises a dinucleotide using an intrinsic 'tape-measure'...
May 3, 2017: Nature Communications
https://www.readbyqxmd.com/read/28460087/base-excision-repair-variants-and-pesticide-exposure-increase-parkinson-s-disease-risk
#6
Laurie H Sanders, Kimberly C Paul, Evan H Howlett, Hakeem Lawal, Sridhar Boppana, Jeff M Bronstein, Beate Ritz, J Timothy Greenamyre
Exposure to certain pesticides induces oxidative stress and increases Parkinson's disease (PD) risk. Mitochondrial DNA (mtDNA) damage is found in dopaminergic neurons in idiopathic PD and following pesticide exposure in experimental models thereof. Base excision repair (BER) is the major pathway responsible for repairing oxidative DNA damage in cells. Whether single nucleotide polymorphisms (SNPs) in BER genes alone or in combination with pesticide exposure influence PD risk is unknown. We investigated the contributions of functional SNPs in 2 BER genes (APEX1 and OGG1) and mitochondrial dysfunction- or oxidative stress-related pesticide exposure, including paraquat, to PD risk...
April 29, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28459532/synergistic-effects-of-an-irreversible-dna-polymerase-inhibitor-and-dna-damaging-agents-on-hela-cells
#7
Rakesh Paul, Samya Banerjee, Marc M Greenberg
DNA repair is vital to maintaining genome integrity but thwarts the effects of cytotoxic agents that target nucleic acids. Consequently, repair enzymes are potential targets for molecules that modulate cell function and anticancer therapeutics. DNA polymerase β (Pol β) is an attractive target because it plays a key role in base excision repair (BER), a primary pathway that repairs the effects of many DNA damaging agents. We previously identified an irreversible inhibitor of Pol β whose design was based upon a DNA lesion that inactivates Pol β and its back up BER enzyme, DNA polymerase λ (Pol λ)...
May 1, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28456802/berbamine-exerts-anti-inflammatory-effects-via-inhibition-of-nf-%C3%AE%C2%BAb-and-mapk-signaling-pathways
#8
Xiao-Jian Jia, Xi Li, Feng Wang, Han-Qing Liu, Da-Jun Zhang, Yun Chen
BACKGROUND/AIMS: This study aimed to investigate the anti-inflammatory activity of Berbamine (BER), a bisbenzylisoquinoline alkaloid extracted from Berberis amurensis (Xiao Bo An), and the underlying mechanisms. METHODS: Macrophages and neutrophils were treated with BER in vitro and stimulated with LPS and fMLP. The effects of BER on the expression of pro-inflammatory mediators in macrophages were evaluated with quantitative RT-PCR and ELISA. The effects of BER on the activation and superoxide release of neutrophils were determined with flow cytometry and WST-1 reduction test...
April 26, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/28439991/melatonin-a-pleiotropic-molecule-that-modulates-dna-damage-response-and-repair-pathways
#9
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/28431926/multiple-repair-pathways-mediate-cellular-tolerance-to-resveratrol-induced-dna-damage
#10
Ying Liu, Xiaohua Wu, Xiaoqing Hu, Ziyuan Chen, Hao Liu, Shunichi Takeda, Yong Qing
Resveratrol (RSV) has been reported to exert health benefits for the prevention and treatment of many diseases, including cancer. The anticancer mechanisms of RSV seem to be complex and may be associated with genotoxic potential. To better understand the genotoxic mechanisms, we used wild-type (WT) and a panel of isogenic DNA-repair deficient DT40 cell lines to identify the DNA damage effects and molecular mechanisms of cellular tolerance to RSV. Our results showed that RSV induced significant formation of γ-H2AX foci and chromosome aberrations (CAs) in WT cells, suggesting direct DNA damage effects...
April 19, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/28415784/misregulation-of-dna-damage-repair-pathways-in-hpv-positive-head-and-neck-squamous-cell-carcinoma-contributes-to-cellular-radiosensitivity
#11
Catherine M Nickson, Parisa Moori, Rachel J Carter, Carlos P Rubbi, Jason L Parsons
Patients with human papillomavirus type 16 (HPV)-associated oropharyngeal squamous cell carcinomas (OPSCC) display increased sensitivity to radiotherapy and improved survival rates in comparison to HPV-negative forms of the disease. However the cellular mechanisms responsible for this characteristic difference are unclear. Here, we have investigated the contribution of DNA damage repair pathways to the in vitro radiosensitivity of OPSCC cell lines. We demonstrate that two HPV-positive OPSCC cells are indeed more radiosensitive than two HPV-negative OPSCC cells, which correlates with reduced efficiency for the repair of ionising radiation (IR)-induced DNA double strand breaks (DSB)...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28391506/inactivation-of-genes-involved-in-base-excision-repair-of-corynebacterium-glutamicum-and-survival-of-the-mutants-in-presence-of-various-mutagens
#12
Fabiola Kautzmann, Josef Altenbuchner
Base Excision Repair (BER) is considered as the most active DNA repair pathway in vivo, which is initiated by recognition of the nucleotide lesions and excision of the damaged DNA base. The genome of Corynebacterium glutamicum ATCC 13032 contains various DNA glycosylases encoding genes (ung, fpg/mutM, tagI, alkA, mutY), two AP-endonuclease encoding genes (nei and nth) and an exonuclease encoding gene xth. To investigate the role of these genes during DNA repair in C. glutamicum, mutants with deletions of one or more genes in BER pathway were created...
April 8, 2017: Archives of Microbiology
https://www.readbyqxmd.com/read/28373211/a-new-sub-pathway-of-long-patch-base-excision-repair-involving-5-gap-formation
#13
Jordan Woodrick, Suhani Gupta, Sharon Camacho, Swetha Parvathaneni, Sujata Choudhury, Amrita Cheema, Yi Bai, Pooja Khatkar, Hayriye Verda Erkizan, Furqan Sami, Yan Su, Orlando D Schärer, Sudha Sharma, Rabindra Roy
Base excision repair (BER) is one of the most frequently used cellular DNA repair mechanisms and modulates many human pathophysiological conditions related to DNA damage. Through live cell and in vitro reconstitution experiments, we have discovered a major sub-pathway of conventional long-patch BER that involves formation of a 9-nucleotide gap 5' to the lesion. This new sub-pathway is mediated by RECQ1 DNA helicase and ERCC1-XPF endonuclease in cooperation with PARP1 poly(ADP-ribose) polymerase and RPA The novel gap formation step is employed during repair of a variety of DNA lesions, including oxidative and alkylation damage...
April 3, 2017: EMBO Journal
https://www.readbyqxmd.com/read/28371273/fen1-promotes-tumor-progression-and-confers-cisplatin-resistance-in-non-small-cell-lung-cancer
#14
Lingfeng He, Libo Luo, Hong Zhu, Huan Yang, Yilan Zhang, Huan Wu, Hongfang Sun, Feng Jiang, Chandra Sekhar Kathera, Lingjie Liu, Ziheng Zhuang, Haoyan Chen, Feiyan Pan, Zhigang Hu, Jing Zhang, Zhigang Guo
Lung cancer is one of the leading causes of cancer mortality worldwide. The therapeutic effect of chemotherapy is limited due to the resistance of cancer cells, which remains a challenge in cancer therapeutics. In this work, we found that flap endonuclease 1 (FEN1) is overexpressed in lung cancer cells. FEN1 is a major component of the base excision repair (BER) pathway for DNA repair systems and plays important roles in maintaining genomic stability through DNA replication and repair. We showed that FEN1 is critical for the rapid proliferation of lung cancer cells...
March 29, 2017: Molecular Oncology
https://www.readbyqxmd.com/read/28357058/how-are-base-excision-dna-repair-pathways-deployed-in-vivo
#15
REVIEW
Upasna Thapar, Bruce Demple
Since the discovery of the base excision repair (BER) system for DNA more than 40 years ago, new branches of the pathway have been revealed at the biochemical level by in vitro studies. Largely for technical reasons, however, the confirmation of these subpathways in vivo has been elusive. We review methods that have been used to explore BER in mammalian cells, indicate where there are important knowledge gaps to fill, and suggest a way to address them.
2017: F1000Research
https://www.readbyqxmd.com/read/28351647/apobec3b-cytidine-deaminase-targets-the-non-transcribed-strand-of-trna-genes-in-yeast
#16
Natalie Saini, Steven A Roberts, Joan F Sterling, Ewa P Malc, Piotr A Mieczkowski, Dmitry A Gordenin
Variations in mutation rates across the genome have been demonstrated both in model organisms and in cancers. This phenomenon is largely driven by the damage specificity of diverse mutagens and the differences in DNA repair efficiency in given genomic contexts. Here, we demonstrate that the single-strand DNA-specific cytidine deaminase APOBEC3B (A3B) damages tRNA genes at a 1000-fold higher efficiency than other non-tRNA genomic regions in budding yeast. We found that A3B-induced lesions in tRNA genes were predominantly located on the non-transcribed strand, while no transcriptional strand bias was observed in protein coding genes...
March 21, 2017: DNA Repair
https://www.readbyqxmd.com/read/28333944/mechanisms-of-glycosylase-induced-genomic-instability
#17
Daniel E Eyler, Kylie A Burnham, Thomas E Wilson, Patrick J O'Brien
Human alkyladenine DNA glycosylase (AAG) initiates base excision repair (BER) to guard against mutations by excising alkylated and deaminated purines. Counterintuitively, increased expression of AAG has been implicated in increased rates of spontaneous mutation in microsatellite repeats. This microsatellite mutator phenotype is consistent with a model in which AAG excises bulged (unpaired) bases, altering repeat length. To directly test the role of base excision in AAG-induced mutagenesis, we conducted mutation accumulation experiments in yeast overexpressing different variants of AAG and detected mutations via high-depth genome resequencing...
2017: PloS One
https://www.readbyqxmd.com/read/28315507/polymorphisms-and-mutations-in-gstp1-rad51-xrcc1-and-xrcc3-genes-in-breast-cancer-patients
#18
Mazhar Salim Al Zoubi, Katia Zavaglia, Chiara Mazanti, Mohammad Al Hamad, Khalid Al Batayneh, Alaa A A Aljabali, Generoso Bevilacqua
BACKGROUND: Genotoxic factors, including ionizing radiation and oxidative stress, are associated with genomic instability and development of breast cancer (BC). The homologous recombination DNA repair (HRR) pathway, base excision repair (BER) mechanism, and antioxidative enzymes are required as defense mechanisms against these DNA damaging agents. GSTP1, XRCC1, XRCC3 and RAD51 proteins are essential components of antioxidation, BER and HRR of DNA, respectively. Deficiencies in BER, HRR and antioxidation pathways are involved in the progression of cancer...
March 6, 2017: International Journal of Biological Markers
https://www.readbyqxmd.com/read/28267381/dynamics-of-5-carboxylcytosine-during-hepatic-differentiation-potential-general-role-for-active-demethylation-by-dna-repair-in-lineage-specification
#19
Lara C Lewis, Peggy Cho Kiu Lo, Jeremy M Foster, Nan Dai, Ivan R Corrêa, Paulina M Durczak, Gary Duncan, Ashley Ramsawhook, Guruprasad Padur Aithal, Chris Denning, Nicholas R F Hannan, Alexey Ruzov
Patterns of DNA methylation (5-methylcytosine, 5mC) are rearranged during differentiation contributing to the regulation of cell type-specific gene expression. TET proteins oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Both 5fC and 5caC can be recognized and excised from DNA by thymine-DNA glycosylase (TDG) followed by the subsequent incorporation of unmodified cytosine into the abasic site via the base excision repair (BER) pathway. We previously demonstrated that 5caC accumulates during lineage specification of neural stem cells (NSCs) suggesting that such active demethylation pathway is operational in this system; however, it is still unknown if TDG/BER-dependent demethylation is used during other types of cellular differentiation...
April 3, 2017: Epigenetics: Official Journal of the DNA Methylation Society
https://www.readbyqxmd.com/read/28266569/ogg1-dna-interactions-facilitate-nf-%C3%AE%C2%BAb-binding-to-dna-targets
#20
Lang Pan, Wenjing Hao, Xu Zheng, Xianlu Zeng, Adeel Ahmed Abbasi, Istvan Boldogh, Xueqing Ba
DNA repair protein counteracting oxidative promoter lesions may modulate gene expression. Oxidative DNA bases modified by reactive oxygen species (ROS), primarily as 7, 8-dihydro-8-oxo-2'-deoxyguanosine (8-oxoG), which is repaired by 8-oxoguanine DNA glycosylase1 (OGG1) during base excision repair (BER) pathway. Because cellular response to oxidative challenge is accompanied by DNA damage repair, we tested whether the repair by OGG1 is compatible with transcription factor binding and gene expression. We performed electrophoretic mobility shift assay (EMSA) using wild-type sequence deriving from Cxcl2 gene promoter and the same sequence bearing a single synthetic 8-oxoG at defined 5' or 3' guanine in runs of guanines to mimic oxidative effects...
March 7, 2017: Scientific Reports
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