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Kouichi Kitamura, Lusheng Que, Miyuki Shimadu, Miki Koura, Yuuki Ishihara, Kousho Wakae, Takashi Nakamura, Koichi Watashi, Takaji Wakita, Masamichi Muramatsu
Hepatitis B virus (HBV) is one of the major etiological pathogens for liver cirrhosis and hepatocellular carcinoma. Chronic HBV infection is a key factor in these severe liver diseases. During infection, HBV forms a nuclear viral episome in the form of covalently closed circular DNA (cccDNA). Current therapies are not able to efficiently eliminate cccDNA from infected hepatocytes. cccDNA is a master template for viral replication that is formed by the conversion of its precursor, relaxed circular DNA (rcDNA)...
June 2018: PLoS Pathogens
Mark J Thompson, Victoria J B Gotham, Barbara Ciani, Jane A Grasby
DNA replication and repair frequently involve intermediate two-way junction structures with overhangs, or flaps, that must be promptly removed; a task performed by the essential enzyme flap endonuclease 1 (FEN1). We demonstrate a functional relationship between two intrinsically disordered regions of the FEN1 protein, which recognize opposing sides of the junction and order in response to the requisite substrate. Our results inform a model in which short-range translocation of FEN1 on DNA facilitates search for the annealed 3'-terminus of a primer strand, which is recognized by breaking the terminal base pair to generate a substrate with a single nucleotide 3'-flap...
June 7, 2018: Nucleic Acids Research
Keiichiro Sakuma, Eiichi Sasaki, Kenya Kimura, Koji Komori, Yasuhiro Shimizu, Yasushi Yatabe, Masahiro Aoki
HNRNPLL (heterogeneous nuclear ribonucleoprotein L-like), an RNA-binding protein that regulates alternative splicing of pre-mRNAs, has been shown to regulate differentiation of lymphocytes, as well as metastasis of colorectal cancer cells. Here we show that HNRNPLL promotes cell cycle progression and hence proliferation of colorectal cancer cells. Functional annotation analysis of those genes whose expression levels were changed by three-fold or more in RNA sequencing analysis between SW480 cells overexpressing HNRNPLL and those knocked down for HNRNPLL revealed enrichment of DNA replication-related genes by HNRNPLL overexpression...
June 5, 2018: Cancer Science
Jordan R Becker, David Gallo, Wendy Leung, Taylor Croissant, Yee Mon Thu, Hai Dang Nguyen, Timothy K Starr, Grant W Brown, Anja-Katrin Bielinsky
Overexpression of the flap endonuclease FEN1 has been observed in a variety of cancer types and is a marker for poor prognosis. To better understand the cellular consequences of FEN1 overexpression we utilized a model of its Saccharomyces cerevisiae homolog, RAD27. In this system, we discovered that flap endonuclease overexpression impedes replication fork progression and leads to an accumulation of cells in mid-S phase. This was accompanied by increased phosphorylation of the checkpoint kinase Rad53 and histone H2A-S129...
May 7, 2018: Nucleic Acids Research
Joel Isohookana, Kirsi-Maria Haapasaari, Ylermi Soini, Joni Leppänen, Peeter Karihtala
BACKGROUND: We studied the expression of some major proteins involved in cell-cycle regulation and DNA repair, the roles of which are not well known in pancreatic ductal adenocarcinoma (PDAC), but which have a significant impact on carcinogenesis of many other cancers. METHODS: We immunohistochemically assessed expression levels of the cell-cycle regulators Rb1, p16 and cyclin-dependent kinase 4 (CDK4), and the DNA repair enzymes O6-methylguanine-DNA-alkyltransferase (MGMT) and flap endonuclease-1 (FEN1) separately in malignant tissue and benign tissue from resection margins in 102 cases of PDAC...
May 1, 2018: Pathology, Research and Practice
Viktoriya Peeva, Daniel Blei, Genevieve Trombly, Sarah Corsi, Maciej J Szukszto, Pedro Rebelo-Guiomar, Payam A Gammage, Alexei P Kudin, Christian Becker, Janine Altmüller, Michal Minczuk, Gábor Zsurka, Wolfram S Kunz
Emerging gene therapy approaches that aim to eliminate pathogenic mutations of mitochondrial DNA (mtDNA) rely on efficient degradation of linearized mtDNA, but the enzymatic machinery performing this task is presently unknown. Here, we show that, in cellular models of restriction endonuclease-induced mtDNA double-strand breaks, linear mtDNA is eliminated within hours by exonucleolytic activities. Inactivation of the mitochondrial 5'-3'exonuclease MGME1, elimination of the 3'-5'exonuclease activity of the mitochondrial DNA polymerase POLG by introducing the p...
April 30, 2018: Nature Communications
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...
May 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...
July 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...
April 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
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