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https://www.readbyqxmd.com/read/28100786/inositol-depletion-induced-by-acute-treatment-of-the-bipolar-disorder-drug-valproate-increases-levels-of-phytosphingosine
#1
Shyamalagauri Jadhav, Sarah Russo, L Ashley Cowart, Miriam L Greenberg
Bipolar disorder (BD) is a severe psychiatric illness affecting ~2% of the world population. Valproate (VPA) and lithium, though widely used for the treatment of BD, are not universally effective. These drugs have been shown to cause inositol depletion, but translating this observation to a specific therapeutic mechanism has been difficult, hampering the development of more effective therapies. We have shown previously in yeast that chronic VPA treatment induces the unfolded protein response due to increasing ceramide levels...
January 18, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28098985/hmgb1-stimulates-activity-of-polymerase-%C3%AE-on-nucleosome-substrates
#2
Angela Balliano, Fanfan Hao, Catherine Njeri, Lata Balakrishnan, Jeffrey J Hayes
The process of base excision repair (BER) recognizes and repairs small lesions or inappropriate bases on DNA through either a short-patch or long-patch pathway. The enzymes involved in BER have been well-characterized on DNA substrates, and, somewhat surprisingly, many of these enzymes, including several DNA glycosylases, AP endonuclease (APE), FEN1 endonuclease, and DNA ligases, have been shown to have activity on DNA substrates within nucleosomes. DNA polymerase β (Pol β), however, exhibits drastically reduced or no activity on nucleosomal DNA...
January 18, 2017: Biochemistry
https://www.readbyqxmd.com/read/28079132/critical-role-for-cafen1-and-cafen12-of-candida-albicans-in-cell-wall-integrity-and-biofilm-formation
#3
Md Alfatah, Vinay K Bari, Anubhav S Nahar, Swati Bijlani, K Ganesan
Sphingolipids are involved in several cellular functions, including maintenance of cell wall integrity. To gain insight into the role of individual genes of sphingolipid biosynthetic pathway, we have screened Saccharomyces cerevisiae strains deleted in these genes for sensitivity to cell wall perturbing agents calcofluor white and congo red. Only deletants of FEN1 and SUR4 genes were found to be sensitive to both these agents. Candida albicans strains deleted in their orthologs, CaFEN1 and CaFEN12, respectively, also showed comparable phenotypes, and a strain deleted for both these genes was extremely sensitive to cell wall perturbing agents...
January 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28034453/dna-damage-repair-in-breast-cancer-and-its-therapeutic-implications
#4
REVIEW
Reem Ali, Emad A Rakha, Srinivasan Madhusudan, Helen E Bryant
The DNA damage response (DDR) involves the activation of numerous cellular activities that repair DNA lesions and maintain genomic integrity, and is critical in preventing tumorigenesis. Inherited or acquired mutations in specific genes involved in the DNA damage response, for example the breast cancer susceptibility genes 1/2 (BRCA1/2), phosphatase and tensin homolog (PTEN) and P53 are associated with various subtypes of breast cancer. Such changes can render breast cancer cells particularly sensitive to specific DNA damage response inhibitors, for example BRCA1/2 germline mutated cells are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors...
December 26, 2016: Pathology
https://www.readbyqxmd.com/read/27866211/single-nucleotide-polymorphisms-of-genes-involved-in-repair-of-oxidative-dna-damage-and-the-risk-of-recurrent-depressive-disorder
#5
Piotr Czarny, Dominik Kwiatkowski, Monika Toma, Piotr Gałecki, Agata Orzechowska, Kinga Bobińska, Anna Bielecka-Kowalska, Janusz Szemraj, Michael Berk, George Anderson, Tomasz Śliwiński
BACKGROUND Depressive disorder, including recurrent type (rDD), is accompanied by increased oxidative stress and activation of inflammatory pathways, which may induce DNA damage. This thesis is supported by the presence of increased levels of DNA damage in depressed patients. Such DNA damage is repaired by the base excision repair (BER) pathway. BER efficiency may be influenced by polymorphisms in BER-related genes. Therefore, we genotyped nine single-nucleotide polymorphisms (SNPs) in six genes encoding BER proteins...
November 20, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/27852524/targeting-dna-flap-endonuclease-1-to-impede-breast-cancer-progression
#6
Lingfeng He, Yilan Zhang, Hongfang Sun, Feng Jiang, Huan Yang, Huan Wu, Ting Zhou, Sencai Hu, Chandra Sekhar Kathera, Xiaojun Wang, Haoyan Chen, Hongzhi Li, Binghui Shen, Yongqiang Zhu, Zhigang Guo
DNA flap endonuclease 1 (FEN1) plays critical roles in maintaining genome stability and integrity by participating in both DNA replication and repair. Suppression of FEN1 in cells leads to the retardation of DNA replication and accumulation of unrepaired DNA intermediates, resulting in DNA double strand breaks (DSBs) and apoptosis. Therefore, targeting FEN1 could serve as a potent strategy for cancer therapy. In this study, we demonstrated that FEN1 is overexpressed in breast cancers and is essential for rapid proliferation of cancer cells...
December 2016: EBioMedicine
https://www.readbyqxmd.com/read/27849570/the-werner-syndrome-helicase-coordinates-sequential-strand-displacement-and-fen1-mediated-flap-cleavage-during-polymerase-%C3%AE-elongation
#7
Baomin Li, Sita Reddy, Lucio Comai
The Werner syndrome protein (WRN) suppresses the loss of telomeres replicated by lagging strand synthesis by a yet to be defined mechanism. Here we show that whereas either WRN or the Bloom syndrome helicase (BLM) stimulate DNA polymerase δ progression across telomeric G-rich repeats, only WRN promotes sequential strand displacement synthesis and FEN1 cleavage, a critical step in Okazaki fragment maturation, at these sequences. Helicase activity as well as the conserved winged-helix (WH) motif and the Helicase-and-RNaseD C-terminal (HRDC) domain play important but distinct roles in this process...
November 14, 2016: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/27832451/expression-data-analysis-for-the-identification-of-potential-biomarker-of-pregnancy-associated-breast-cancer
#8
Raja Rajeswary Thanmalagan, Leimarembi Devi Naorem, Amouda Venkatesan
Breast cancer affects every 1 of 3000 pregnant women or in the first post-partum year is referred as Pregnancy Associated Breast Cancer (PABC) in mid 30s. Even-though rare disease, classified under hormone receptor negative status which metastasis quickly to other parts by extra cellular matrix degradation. Hence it is important to find an optimal treatment option for a PABC patient. Also additional care should be taken to choose the drug; in order to avoid fetal malformation and post-partum stage side-effects...
November 10, 2016: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/27801669/fen1-gene-variants-confer-reduced-risk-of-breast-cancer-in-chinese-women-a-case-control-study
#9
Shuai Lin, Meng Wang, Xinghan Liu, Ye Lu, Zhuoqing Gong, Yan Guo, Pengtao Yang, Tian Tian, Cong Dai, Yi Zheng, Peng Xu, Shanli Li, Yuyao Zhu, Zhijun Dai
This study aimed to assess the associations of two common Flap endonuclease 1 (FEN1) polymorphisms (rs4246215 and rs174538) with breast cancer risk in northwest Chinese women. We conducted a case-control study with 560 breast cancer patients and 583 age-matched healthy controls from Northwest China. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to estimate the associations. We found a significantly reduced risk of breast cancer associated with T allele of rs4246215 (allele model: OR 0.81, 95% CI 0...
October 27, 2016: Oncotarget
https://www.readbyqxmd.com/read/27793507/proliferating-cell-nuclear-antigen-prevents-trinucleotide-repeat-expansions-by-promoting-repeat-deletion-and-hairpin-removal
#10
Jill M Beaver, Yanhao Lai, Shantell J Rolle, Yuan Liu
DNA base lesions and base excision repair (BER) within trinucleotide repeat (TNR) tracts modulate repeat instability through the coordination among the key BER enzymes DNA polymerase β, flap endonuclease 1 (FEN1) and DNA ligase I (LIG I). However, it remains unknown whether BER cofactors can also alter TNR stability. In this study, we discovered that proliferating cell nuclear antigen (PCNA), a cofactor of BER, promoted CAG repeat deletion and removal of a CAG repeat hairpin during BER in a duplex CAG repeat tract and CAG hairpin loop, respectively...
October 22, 2016: DNA Repair
https://www.readbyqxmd.com/read/27759916/physical-and-functional-interactions-between-nucleosomes-and-rad27-a-critical-component-of-dna-processing-during-dna-metabolism
#11
EDITORIAL
Buki Kwon, Palinda Ruvan Munashingha, Yong-Keol Shin, Chul-Hwan Lee, Bing Li, Yeon-Soo Seo
Highly conserved eukaryotic histones are polybasic proteins that package DNA into nucleosomes, a building block of chromatin, allowing extremely long DNA molecules to form compact and discrete chromosomes. The histone N-terminal tails that extend from the nucleosome core act as docking sites for many proteins through diverse post-translational modifications, regulating various DNA transactions. In this report, we present evidence that the nucleosomes can positively regulate the enzymatic activity of Rad27 (yeast Fen1), a major processing enzyme important for Okazaki fragment in eukaryotes...
December 2016: FEBS Journal
https://www.readbyqxmd.com/read/27706618/identification-of-key-biomarkers-involved-in-osteosarcoma-using-altered-modules
#12
Z Z Liu, S T Cui, B Tang, Z Z Wang, Z X Luan
The aim of this study was to screen for key biomarkers of osteosarcoma (OS) by tracking altered modules. Protein-protein interaction (PPI) networks of OS and normal groups were constructed and re-weighted using the Pearson correlation coefficient (PCC), respectively. The condition-specific modules were explored from OS and normal PPI networks using a clique-merging algorithm. Altered modules were identified by a maximum weight bipartite-matching method. The important biological pathways in OS were identified by a pathway-enrichment analysis using genes from disrupted modules...
August 26, 2016: Genetics and Molecular Research: GMR
https://www.readbyqxmd.com/read/27699013/fen1-69g-a-and-4150g-t-polymorphisms-and-breast-cancer-risk
#13
Maryam Rezaei, Mohammad Hashemi, Sara Sanaei, Mohammad Ali Mashhadi, Seyed Mehdi Hashemi, Gholamreza Bahari, Mohsen Taheri
Flap endonuclease 1 (FEN1), a DNA repair protein, is important in preventing carcinogenesis. Two functional germ line variants -69G>A (rs174538) and +4150G>T (rs4246215) in the FEN1 gene have been associated with risk of various types of cancer. The aim of the present study was to evaluate the possible impact of FEN1 polymorphisms on risk of breast cancer (BC) in a sample of Iranian subjects. The FEN1 -69G>A and +4150G>T polymorphisms were analyzed in a case-control study that included 266 BC patients and 225 healthy females...
October 2016: Biomedical Reports
https://www.readbyqxmd.com/read/27694478/role-of-fen1-s187-phosphorylation-in-counteracting-oxygen-induced-stress-and-regulating-postnatal-heart-development
#14
Lina Zhou, Huifang Dai, Jian Wu, Mian Zhou, Hua Yuan, Juan Du, Lu Yang, Xiwei Wu, Hong Xu, Yuejin Hua, Jian Xu, Li Zheng, Binghui Shen
Flap endonuclease 1 (FEN1) phosphorylation is proposed to regulate the action of FEN1 in DNA repair as well as Okazaki fragment maturation. However, the biologic significance of FEN1 phosphorylation in response to DNA damage remains unknown. Here, we report an in vivo role for FEN1 phosphorylation, using a mouse line carrying S187A FEN1, which abolishes FEN1 phosphorylation. Although S187A mouse embryonic fibroblast cells showed normal proliferation under low oxygen levels (2%), the mutant cells accumulated oxidative DNA damage, activated DNA damage checkpoints, and showed G1-phase arrest at atmospheric oxygen levels (21%)...
January 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27590340/valproate-induces-the-unfolded-protein-response-by-increasing-ceramide-levels
#15
Shyamalagauri Jadhav, Sarah Russo, Stéphanie Cottier, Roger Schneiter, Ashley Cowart, Miriam L Greenberg
Bipolar disorder (BD), which is characterized by depression and mania, affects 1-2% of the world population. Current treatments are effective in only 40-60% of cases and cause severe side effects. Valproate (VPA) is one of the most widely used drugs for the treatment of BD, but the therapeutic mechanism of action of this drug is not understood. This knowledge gap has hampered the development of effective treatments. To identify candidate pathways affected by VPA, we performed a genome-wide expression analysis in yeast cells grown in the presence or absence of the drug...
October 14, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27526030/cellularly-active-n-hydroxyurea-fen1-inhibitors-block-substrate-entry-to-the-active-site
#16
Jack C Exell, Mark J Thompson, L David Finger, Steven J Shaw, Judit Debreczeni, Thomas A Ward, Claire McWhirter, Catrine L B Siöberg, Daniel Martinez Molina, W Mark Abbott, Clifford D Jones, J Willem M Nissink, Stephen T Durant, Jane A Grasby
The structure-specific nuclease human flap endonuclease-1 (hFEN1) plays a key role in DNA replication and repair and may be of interest as an oncology target. We present the crystal structure of inhibitor-bound hFEN1, which shows a cyclic N-hydroxyurea bound in the active site coordinated to two magnesium ions. Three such compounds had similar IC50 values but differed subtly in mode of action. One had comparable affinity for protein and protein-substrate complex and prevented reaction by binding to active site catalytic metal ions, blocking the necessary unpairing of substrate DNA...
October 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27467592/cell-killing-mechanisms-and-impact-on-gene-expression-by-gemcitabine-and-212pb-trastuzumab-treatment-in-a-disseminated-i-p-tumor-model
#17
Kwon Joong Yong, Diane E Milenic, Kwamena E Baidoo, Martin W Brechbiel
In pre-clinical studies, combination therapy with gemcitabine and targeted radioimmunotherapy (RIT) using 212Pb-trastuzumab showed tremendous therapeutic potential in the LS-174T tumor xenograft model of disseminated intraperitoneal disease. To better understand the underlying molecular basis for the observed cell killing efficacy, gene expression profiling was performed after a 24 h exposure to 212Pb-trastuzumab upon gemcitabine (Gem) pre-treatment in this model. DNA damage response genes in tumors were quantified using a real time quantitative PCR array (qRT-PCR array) covering 84 genes...
2016: PloS One
https://www.readbyqxmd.com/read/27455635/shape-dependent-genotoxicity-of-mesoporous-silica-nanoparticles-and-cellular-mechanisms
#18
Meng Niu, Hongshan Zhong, Haibo Shao, Duo Hong, Tengchuang Ma, Ke Xu, Xiaowei Chen, Jinhang Han, Jun Sun
Although mesoporous silica nanoparticles (MSNs) are widely used in food products, cosmetics and nanomedicines as vector for drug delivery, data on their potential genotoxocity are limited. The aim of this study was to investigate the cytotoxic and genotoxic potentials of MSNs of different shapes, and to establish a high-throughput screening method for nanoparticles. We used functional macrophage receptor with collagenous structure (MARCO)-expressing DNA repair deficient chicken DT40 cells, which are designed to internalize nanoparticles and to be deficient in several specific DNA repair pathways...
March 2016: Journal of Nanoscience and Nanotechnology
https://www.readbyqxmd.com/read/27452117/lysine-acetylation-and-succinylation-in-hela-cells-and-their-essential-roles-in-response-to-uv-induced-stress
#19
Hong Xu, Xuanyi Chen, Xiaoli Xu, Rongyi Shi, Shasha Suo, Kaiying Cheng, Zhiguo Zheng, Meixia Wang, Liangyan Wang, Ye Zhao, Bing Tian, Yuejin Hua
Lysine acetylation and succinylation are major types of protein acylation that are important in many cellular processes including gene transcription, cellular metabolism, DNA damage response. Malfunctions in these post-translational modifications are associated with genome instability and disease in higher organisms. In this study, we used high-resolution nano liquid chromatography-tandem mass spectrometry combined with affinity purification to quantify the dynamic changes of protein acetylation and succinylation in response to ultraviolet (UV)-induced cell stress...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27391345/increasing-sensitivity-to-dna-damage-is-a-potential-driver-for-human-ovarian-cancer
#20
Yimei Jin, Xin Xu, Xuemeng Wang, Henry Kuang, Michael Osterman, Shi Feng, Deqiang Han, Yu Wu, Mo Li, Hongyan Guo
Ovarian cancer is one of the most common cancers among women, accounting for more deaths than any other gynecological diseases. However, the survival rate for ovarian cancer has not essentially improved over the past thirty years. Thus, to understand the molecular mechanism of ovarian tumorigenesis is important for optimizing the early diagnosis and treating this disease. In this study, we observed obvious DNA lesions, especially DNA double strand breaks (DSBs) accompanying cell cycle checkpoint activation, in the human epithelial ovarian cancer samples, which could be due to the impaired DNA response machinery...
August 2, 2016: Oncotarget
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