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S M Müller, H Finke, F Ebert, J F Kopp, F Schumacher, B Kleuser, K A Francesconi, G Raber, T Schwerdtle
Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsHCs (AsHC 332 and AsHC 360) on the expression of 44 genes covering DNA repair, stress response, cell death, autophagy, and epigenetics via RT-qPCR in human liver (HepG2) cells. Both AsHCs affected the gene expression, but to different extents...
March 30, 2018: Archives of Toxicology
Chi-Chiu Lee, Tao-Shih Hsieh
Wuho known as WDR4 encodes a highly conserved WD40-repeat protein, which has known homologues of WDR4 in human and mouse. Wuho-FEN1 interaction may have a critical role in the growth and development, and in the maintenance of genome stability. However, how Wuho gene deletion contributes to cell growth inhibition and apoptosis is still unknown. We utilized CAGGCre-ER transgenic mice have a tamoxifen-inducible cre-mediated recombination cassette to prepare primary mouse embryonic fibroblasts (MEFs) with Wuho deficiency...
March 21, 2018: Cellular Signalling
Jiao Zou, Linlin Zhu, Xiaomei Jiang, Yang Wang, Yue Wang, Xiangwei Wang, Bin Chen
Flap endonuclease 1 (FEN1) overexpression promotes breast cancer. We investigated the role of FEN1 in cisplatin resistance and the chemosensitizing effects of curcumin in breast cancer cells. We demonstrated that FEN1 overexpression promotes cisplatin resistance in breast cancer cells, and that FEN1 knockdown enhances cisplatin sensitivity. Curcumin down-regulated FEN1 expression in a dose-dependent manner. A combination of cisplatin and curcumin enhanced breast cancer cell sensitivity to cisplatin by down-regulating FEN1 expression in vitro and in vivo ...
February 16, 2018: Oncotarget
Qiao Wang, Xiuxiu Du, Ke Ma, Ping Shi, Wenbin Liu, Jing Sun, Min Peng, Zhiwei Huang
Elongases FEN1/ELO2 and SUR4/ELO3 are important enzymes involved in the elongation of long-chain fatty acids (LCFAs) to very long-chain fatty acids (VLCFAs) in Saccharomyces cerevisiae. The molecular mechanism of the involvement of these elongases in lipotoxicity is unclear. In the present study, we investigated the role of VLCFA elongases in oleic acid-mediated yeast cytotoxicity. The spot test showed that yeast strains with the deletion of ELO2 or ELO3 were strikingly sensitive to oleic acid, while there was no change on the growth of strain with deleted ELO1 which was involved in the elongation of C14 fatty acid (FA) to C16 FA...
March 2018: Microbiological Research
Yijin Liu, Alasdair Freeman, Anne-Cécile Déclais, Anton Gartner, David M J Lilley
Four-way Holliday junctions in DNA are the central intermediates of genetic recombination and must be processed into regular duplex species. One mechanism for achieving this is called resolution, brought about by structure-selective nucleases. GEN1 is an important junction-resolving enzyme in eukaryotic cells, a member of the FEN1/EXO1 superfamily of nucleases. While human GEN1 is difficult to work with because of aggregation, orthologs from thermophilic fungi have been identified using bioinformatics and have proved to have excellent properties...
2018: Methods in Enzymology
Manal S Zaher, Fahad Rashid, Bo Song, Luay I Joudeh, Mohamed A Sobhy, Muhammad Tehseen, Manju M Hingorani, Samir M Hamdan
RNA-DNA hybrid primers synthesized by low fidelity DNA polymerase α to initiate eukaryotic lagging strand synthesis must be removed efficiently during Okazaki fragment (OF) maturation to complete DNA replication. In this process, each OF primer is displaced and the resulting 5'-single-stranded flap is cleaved by structure-specific 5'-nucleases, mainly Flap Endonuclease 1 (FEN1), to generate a ligatable nick. At least two models have been proposed to describe primer removal, namely short- and long-flap pathways that involve FEN1 or FEN1 along with Replication Protein A (RPA) and Dna2 helicase/nuclease, respectively...
February 6, 2018: Nucleic Acids Research
Junhua Zhao, Guliang Wang, Imee M Del Mundo, Jennifer A McKinney, Xiuli Lu, Albino Bacolla, Stephen B Boulware, Changsheng Zhang, Haihua Zhang, Pengyu Ren, Catherine H Freudenreich, Karen M Vasquez
Sequences with the capacity to adopt alternative DNA structures have been implicated in cancer etiology; however, the mechanisms are unclear. For example, H-DNA-forming sequences within oncogenes have been shown to stimulate genetic instability in mammals. Here, we report that H-DNA-forming sequences are enriched at translocation breakpoints in human cancer genomes, further implicating them in cancer etiology. H-DNA-induced mutations were suppressed in human cells deficient in the nucleotide excision repair nucleases, ERCC1-XPF and XPG, but were stimulated in cells deficient in FEN1, a replication-related endonuclease...
January 30, 2018: Cell Reports
Lingfeng He, Huan Yang, Shiying Zhou, Hong Zhu, Huiwen Mao, Zhuang Ma, Ting Wu, Alagamuthu Karthick Kumar, Chandrasekhar Kathera, Avilala Janardhan, Feiyan Pan, Zhigang Hu, Yanhua Yang, Libo Luo, Zhigang Guo
Studies on cervical cancer are urgently required to improve clinical outcomes. As a major anticancer drug for cervical cancer, paclitaxel has been used for many years in clinical therapy but its therapeutic efficacy is limited by common obstacle from cancer cells. The enhanced DNA repair pathways of cancer cells have been proved to survive DNA damage induced by chemotherapeutic drug. Inhibitors of specific DNA repair pathway can sensitize cancer cells to the treatment of chemotherapeutic drugs. In this paper we found that the effect of paclitaxel can be significantly improved when used in combination with FEN1 inhibitor SC13, suggesting a synergistic mechanism between the two compounds...
March 2018: DNA Repair
Jing Wang, Ping Cao, Yuan-Yuan Qi, Xue-Ping Chen, Li Ma, Rong-Rong Deng, Li-Li Zhang, Yu Zhao
OBJECTIVE: This study aims to evaluate the role of FEN1 E160D mutation in lupus nephritis (LN) patients with cell apoptosis dysfunction. METHODS: (1) Cell apoptosis was detected from 50 paraffin samples obtained from renal biopsies of patients with Class IV LN by TUNEL method and the relationship of the systemic lupus erythematosus disease activity index 2000 (SLEDAI 2000) and renal tissue cell apoptotic index (AI) was discussed. (2) FEN1 gene 61563142-61563342 containing E160D were analysed by extracting genomic DNA from peripheral blood collected from the above 50 LN patients and 25 patients with nephrectomy caused by renal trauma...
December 2017: Autoimmunity
An-Kuo Chou, Ming-Yi Shen, Fang-Yu Chen, Chieh-Lun Hsiao, Liang-Chun Shih, Wen-Shin Chang, Chia-Wen Tsai, Tsung-Ho Ying, Ming-Hsien Wu, Chung-Yu Huang, DA-Tian Bau
BACKGROUND/AIM: Flap endonuclease 1 (FEN1), a protein with multiple functions in genome stability maintenance, is important in cancer prevention. The two functional germline variants of FEN1, rs174538 and rs4246215, regarding cancer susceptibility have been reported in lung, breast, liver, esophageal, gastric, colorectal cancer, glioma and leukemia, but not endometriosis. In this study, we firstly aimed at evaluating the contribution of FEN1 genotypes to endometriosis risk in a representative Taiwan population...
November 2017: Cancer Genomics & Proteomics
Keqiang Zhang, Sawa Keymeulen, Rebecca Nelson, Tommy R Tong, Yate-Ching Yuan, Xinwei Yun, Zheng Liu, Joshua Lopez, Dan J Raz, Jae Y Kim
Flap endonuclease 1 (FEN1) plays a crucial role in both DNA replication and damage repair. In this study, FEN1 expression and its clinical-pathologic significance in non-small-cell lung cancer (NSCLC) was investigated. Quantitative RT-PCR and immunohistochemistry analysis identified that both FEN1 mRNA and protein were highly overexpressed in about 36% of 136 cancer tissues compared to adjacent tissues, in which FEN1 was generally undetectable. Notably, patients with FEN1-overexpressed cancers were prone to have poor differentiation and poor prognosis...
January 2018: American Journal of Pathology
Tianlong Liu, Tiejun Zhang, Feng Zhou, Jitao Wang, Xiaohu Zhai, Nan Mu, Jongsun Park, Minna Liu, Wenxing Liu, Peijin Shang, Yi Ding, Aidong Wen, Yuwen Li
BACKGROUND: Glioblastoma is the most common and aggressive brain tumor associated with a poor prognosis. Plant homeodomain finger protein 20 (PHF20) is highly expressed in primary human gliomas and its expression is associated with tumor grade. However, the molecular mechanism by which PHF20 regulates glioblastoma remains poorly understood. METHODS: Genome wide gene expression analysis was performed to identify differentially expressed genes (DEGs) in U87 cells with PHF20 gene knockdown...
2017: Cancer Cell International
Palaniraja Thandapani, Anthony M Couturier, Zhenbao Yu, Xing Li, Jean-François Couture, Shawn Li, Jean-Yves Masson, Stéphane Richard
The DNA damage response (DDR) is central to the cell survival and it requires post-translational modifications, in part, to sense the damage, amplify the signaling response and recruit and regulate DNA repair enzymes. Lysine methylation of histones such as H4K20 and non-histone proteins including p53 has been shown to be essential for the mounting of the DDR. It is well-known that the lysine methyltransferase SET7 regulates the DDR, as cells lacking this enzyme are hypersensitive to chemotherapeutic drugs. To define addition substrates of SET7 involved in the DDR, we screened a peptide array encompassing potential lysine methylation sites from >100 key DDR proteins and identified peptides from 58 proteins to be lysine methylated defining a methylation consensus sequence of [S>K-2 ; S>R-1 ; K0 ] consistent with previous findings...
September 12, 2017: Oncotarget
Nan Sheng, Yinjiao Ma, Jianping Wang, Bingjie Zou, Guohua Zhou
Flap endonuclease 1 (FEN1) is an endonuclease that catalyzes invasive reaction. It can be used in signal-amplification reaction-based nucleic acid assay. However, the application of FEN1 is hampered due to the lack of detailed protocols to express and purify the enzyme, and to quantify the enzyme activity. In this paper, the DNA fragment coding the gene of FEN1 from Archaeoglobus fulgidus was synthesized, and inserted into the plasmid of pET24a(+) to express recombinant FEN1 with His-tag. After optimizing the expression, detailed expression protocol of FEN1 was obtained by culturing the recombinant E...
October 25, 2016: Sheng Wu Gong Cheng Xue Bao, Chinese Journal of Biotechnology
Sumita Omer, Bar Lavi, Piotr A Mieczkowski, Shay Covo, Einat Hazkani-Covo
Okazaki fragments that are formed during lagging strand DNA synthesis include an initiating primer consisting of both RNA and DNA. The RNA fragment must be removed before the fragments are joined. In Saccharomyces cerevisiae , a key player in this process is the structure-specific flap endonuclease, Rad27p (human homolog FEN1). To obtain a genomic view of the mutational consequence of loss of RAD27 , a S. cerevisiae rad27 Δ strain was subcultured for 25 generations and sequenced using Illumina paired-end sequencing...
November 6, 2017: G3: Genes—Genomes—Genetics
Melike Çaglayan, Rajendra Prasad, Rachel Krasich, Matthew J Longley, Kei Kadoda, Masataka Tsuda, Hiroyuki Sasanuma, Shunichi Takeda, Keizo Tano, William C Copeland, Samuel H Wilson
Mitochondrial aprataxin (APTX) protects the mitochondrial genome from the consequence of ligase failure by removing the abortive ligation product, i.e. the 5'-adenylate (5'-AMP) group, during DNA replication and repair. In the absence of APTX activity, blocked base excision repair (BER) intermediates containing the 5'-AMP or 5'-adenylated-deoxyribose phosphate (5'-AMP-dRP) lesions may accumulate. In the current study, we examined DNA polymerase (pol) γ and pol β as possible complementing enzymes in the case of APTX deficiency...
September 29, 2017: Nucleic Acids Research
Xue Zeng, Xiaofang Che, Yun-Peng Liu, Xiu-Juan Qu, Lu Xu, Chen-Yang Zhao, Chun-Lei Zheng, Ke-Zuo Hou, Yuee Teng
Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the expression of FEN1, and FEN1 knockdown significantly enhanced the sensitivity of BT474 cells to trastuzumab (P<0...
October 2017: Experimental and Therapeutic Medicine
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...
October 2017: Toxicology and Industrial Health
Lingfeng He, Libo Luo, Hong Zhu, Huan Yang, Yilan Zhang, Huan Wu, Hongfang Sun, Feng Jiang, Chandra S Kathera, Lingjie Liu, Ziheng Zhuang, Haoyan Chen, Feiyan Pan, Zhigang Hu, Jing Zhang, Zhigang Guo
No abstract text is available yet for this article.
September 2017: Molecular Oncology
Jia Zhou, Jany Chan, Marie Lambelé, Timur Yusufzai, Jason Stumpff, Patricia L Opresko, Markus Thali, Susan S Wallace
Oxidative damage to telomere DNA compromises telomere integrity. We recently reported that the DNA glycosylase NEIL3 preferentially repairs oxidative lesions in telomere sequences in vitro. Here, we show that loss of NEIL3 causes anaphase DNA bridging because of telomere dysfunction. NEIL3 expression increases during S phase and reaches maximal levels in late S/G2. NEIL3 co-localizes with TRF2 and associates with telomeres during S phase, and this association increases upon oxidative stress. Mechanistic studies reveal that NEIL3 binds to single-stranded DNA via its intrinsically disordered C terminus in a telomere-sequence-independent manner...
August 29, 2017: Cell Reports
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