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DNA replication

Kit Man Wong, Lindsey N Micel, Heather M Selby, Aik Choon Tan, Todd M Pitts, Stacey M Bagby, Anna Spreafico, Peter J Klauck, Stephen J Blakemore, Peter F Smith, Alice McDonald, Allison Berger, John J Tentler, S Gail Eckhardt
Background The neddylation pathway conjugates NEDD8 to cullin-RING ligases and controls the proteasomal degradation of specific proteins involved in essential cell processes. Pevonedistat (MLN4924) is a selective small molecule targeting the NEDD8-activating enzyme (NAE) and inhibits an early step in neddylation, resulting in DNA re-replication, cell cycle arrest and death. We investigated the anti-tumor potential of pevonedistat in preclinical models of melanoma. Methods Melanoma cell lines and patient-derived tumor xenografts (PDTX) treated with pevonedistat were assessed for viability/apoptosis and tumor growth, respectively, to identify sensitive/resistant models...
October 25, 2016: Investigational New Drugs
Gabor Kiraly, Athene S Simonyi, Melinda Turani, Istvan Juhasz, Gabor Nagy, Gaspar Banfalvi
In early S phase the newly replicated DNA is folded back to increasingly compact structures. The process of chromatin condensation inside the nucleus starts with the formation of a micronucleus observed in five established cell lines (K562, CHO, Indian muntjac, murine preB and SCC). Supercoiling of chromatin generates a polarized end-plate region extruded from the nucleus. The extruded chromatin is turned around itself forming the head portion (micronucleus) visible by fluorescence microscopy until the middle of S phase when chromatin structures are succeeded by distinguishable early forms of chromosomes...
October 25, 2016: Apoptosis: An International Journal on Programmed Cell Death
Tanja Stachon, Krasimir Kolev, Zsuzsa Flaskó, Berthold Seitz, Achim Langenbucher, Nóra Szentmáry
PURPOSE: Keratoconus (KC) is a disease characterized by thinning and deformation of the cornea, but its etiology remains unknown. Seventy percent of the corneal stroma consists of collagen, which is composed of three intertwined polypeptide chains with glycine-hydroxyproline-proline repeats along their sequence. Arginase is a cytoplasmatic enzyme and catalyzes the conversion of arginine to urea and ornithine, which serves as a precursor for the endogenous synthesis of proline and hydroxyproline...
October 25, 2016: Graefe's Archive for Clinical and Experimental Ophthalmology
Ziqiang Wang, Ping Fan, Yiwan Zhao, Shikuan Zhang, Jinhua Lu, Weidong Xie, Yuyang Jiang, Fan Lei, Naihan Xu, Yaou Zhang
Nuclear paraspeckle assembly transcript 1 (NEAT1) is the crucial structural platform of paraspeckles, which is one type of nuclear bodies. As a stress-induced lncRNA, the expression of NEAT1 increases in response to viral infection, but little is known about the role of NEAT1 or paraspeckles in the replication of herpes simplex virus-1 (HSV-1). Here, we demonstrate that HSV-1 infection increases NEAT1 expression and paraspeckle formation in a STAT3-dependent manner. NEAT1 and other paraspeckle protein components, P54nrb and PSPC1, can associate with HSV-1 genomic DNA...
October 25, 2016: Cellular and Molecular Life Sciences: CMLS
Jiaqian Pan, Shuangmei Tong, Lei Kang, Jing Tang
PURPOSE OF REVIEW: Although available therapies can effectively inhibit hepatitis B virus (HBV) replication in patients with active chronic hepatitis B (CHB) infection, therapeutic efficacy is limited because of potential drug resistance, and an inability to mediate viral clearance and to rectify immune impairment in CHB patients. This review will summarize the state-of-the-art for anti-HBV drugs and focus on potential drugs and targets under development and evaluation. RECENT FINDINGS: New developing drugs are evaluated for their antiviral effects in the areas of interference with the viral replication cycle, elimination of covalently closed circular DNA, modulation of host immunity and identification of the La protein and its regulator casein kinase as possible targets for the development of anti-HBV therapies...
December 2016: Current Opinion in Infectious Diseases
Wim Trypsteen, Pejman Mohammadi, Clarissa Van Hecke, Pieter Mestdagh, Steve Lefever, Yvan Saeys, Pieter De Bleser, Jo Vandesompele, Angela Ciuffi, Linos Vandekerckhove, Ward De Spiegelaere
Studying the effects of HIV infection on the host transcriptome has typically focused on protein-coding genes. However, recent advances in the field of RNA sequencing revealed that long non-coding RNAs (lncRNAs) add an extensive additional layer to the cell's molecular network. Here, we performed transcriptome profiling throughout a primary HIV infection in vitro to investigate lncRNA expression at the different HIV replication cycle processes (reverse transcription, integration and particle production). Subsequently, guilt-by-association, transcription factor and co-expression analysis were performed to infer biological roles for the lncRNAs identified in the HIV-host interplay...
October 26, 2016: Scientific Reports
Kristelle Desfossés-Baron, Ian Hammond-Martel, Antoine Simoneau, Adnane Sellam, Stephen Roberts, Hugo Wurtele
The mechanism of action of valproate (VPA), a widely prescribed short chain fatty acid with anticonvulsant and anticancer properties, remains poorly understood. Here, the yeast Saccharomyces cerevisiae was used as model to investigate the biological consequences of VPA exposure. We found that low pH strongly potentiates VPA-induced growth inhibition. Transcriptional profiling revealed that under these conditions, VPA modulates the expression of genes involved in diverse cellular processes including protein folding, cell wall organisation, sexual reproduction, and cell cycle progression...
October 26, 2016: Scientific Reports
Kirsi Määttä, Tommi Rantapero, Anna Lindström, Matti Nykter, Minna Kankuri-Tammilehto, Satu-Leena Laasanen, Johanna Schleutker
A remarkable proportion of factors causing genetic predisposition to breast cancer (BC) are unknown in non-BRCA1/2 families. Exome sequencing was performed for 13 high-risk Finnish hereditary breast and/or ovarian cancer (HBOC) families to detect variants contributing to BC susceptibility. After filtering, 18 candidate variants in DNA damage response (DDR) pathway genes were screened in 129 female HBOC patients, up to 989 female controls, and 31 breast tumours by Sanger sequencing/TaqMan assays. In addition, two variants were further studied in 49 male BC patients and 909 male controls...
October 26, 2016: European Journal of Human Genetics: EJHG
Tetsuro Komatsu, Kyosuke Nagata, Harald Wodrich
In recent years, it has been suggested that host cells exert intrinsic mechanisms to control nuclear replicating DNA viruses. This cellular response involves nuclear antiviral factors targeting incoming viral genomes. Herpes simplex virus-1 (HSV-1) is the best-studied model in this context, and it was shown that upon nuclear entry HSV-1 genomes are immediately targeted by components of promyelocytic leukemia nuclear bodies (PML-NBs) and the nuclear DNA sensor IFI16 (interferon gamma inducible protein 16). Based on HSV-1 studies, together with limited examples in other viral systems, these phenomena are widely believed to be a common cellular response to incoming viral genomes, although formal evidence for each virus is lacking...
October 22, 2016: Viruses
Brian Budke, Wei Lv, Alan P Kozikowski, Philip P Connell
Homologous recombination (HR) is an evolutionarily conserved DNA repair process. Overexpression of the key HR protein RAD51 is a common feature of malignant cells. RAD51 plays two distinct genome-stabilizing roles, including HR-mediated repair of double-strand breaks (DSBs) and the promotion of replication fork stability during replication stress. Because upregulation of RAD51 in cancer cells can promote tumor resistance to DNA-damaging oncologic therapies, we and others have worked to develop cancer therapeutics that target various aspects of RAD51 protein function...
October 26, 2016: ChemMedChem
Maud Mavigner, S Thera Lee, Jakob Habib, Cameron Robinson, Guido Silvestri, Una O'Doherty, Ann Chahroudi
OBJECTIVES: Although antiretroviral therapy (ART) effectively suppresses HIV-1 replication, it does not eradicate the virus and ART interruption consistently results in rebound of viraemia, demonstrating the persistence of a long-lived viral reservoir. Several approaches aimed at reducing virus persistence are being developed, and accurate measurements of the latent reservoir (LR) are necessary to assess the effectiveness of anti-latency interventions. We sought to measure the LR in SIV/SHIV-infected rhesus macaques (RMs) by quantifying integrated SIV-DNA...
October 5, 2016: Journal of Virus Eradication
Wei-Ming Li, Chun-Nung Huang, Hung-Lung Ke, Ching-Chia Li, Yu-Ching Wei, Hsin-Chih Yeh, Lin-Li Chang, Chun-Hsiung Huang, Peir-In Liang, Bi-Wen Yeh, Ti-Chun Chan, Chien-Feng Li, Wen-Jeng Wu
Urothelial carcinoma (UC) occurs in the upper urinary tract (UTUC) and the urinary bladder (UBUC). The molecular pathogenesis of UC has not been fully elucidated. Through data mining of a published transcriptome of UBUC (GSE31684), we identified Minichromosome Maintenance Complex Component 2 (MCM2) and MCM10 as the two most significantly upregulated genes in UC progression among the MCM gene family, the key factors for the initiation of DNA replication. To validate the clinical significance of MCM2 and MCM10, immunohistochemistry, evaluated by H-score, was used in a pilot study of 50 UTUC and 50 UBUC samples...
October 21, 2016: Oncotarget
Pablo Gella, Margarita Salas, Mario Mencía
Many different DNA delivery vehicles have been developed and tested, all with their advantages and disadvantages. The bacteriophage phi29 terminal protein (TP) is covalently linked to the 5' ends of the phage genome during the DNA replication process. Our approach is to utilize this TP as a platform to incorporate different protein or peptide modules that can target the DNA to the interior of the cell, to the nucleus, or even to subcellular compartments. In order to be able to insert different peptide modules on the TP sequence to endow it with desired functions and/or eliminate unwanted regions of the protein, we have carried out a transposition screening to detect insertion-permissive points on the sequence of the TP...
2016: PloS One
Wei Gao, Mei-Hong Wu, Ning Wang, Ming-Zheng Ying, Ying-Yi Zhang, Jing Hua, Liu Chuan, Ya-Jie Wang
Previous studies have reported that triple-negative breast cancer is more sensitive to cytotoxic treatment, compared with estrogen receptor (ER)‑positive cancer. However, the underlying molecular mechanisms remain to be fully elucidated. In the present study, we employed reverse transcription‑quantitative polymerase chain reaction, western blot and in vivo assays to investigate the underlying mechanisms. The sensitivities of cells to cisplatin were examined in ER-positive and ER‑negative breast cancer cells, and it was found that the ER‑negative cells were more sensitive to cisplatin, compared with the ER‑positive cells...
October 25, 2016: Molecular Medicine Reports
Wenjie Li, Fei Cao, Juan Li, Zhixin Wang, Yu Ren, Zheyong Liang, Peijun Liu
Simvastatin (SIM), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, has been reported to inhibit the activity of hepatitis B virus (HBV), however, the mechanism underlying its antiviral function remains unknown. Minichromosome maintenance (MCM) 7, a component of the MCM complex, has been reported to act as an important host factor aiding virus genome replication in host cells. The present study demonstrated that downregulation of MCM7 inhibited the expression of proteins transferred by adenoviral vectors...
October 20, 2016: Molecular Medicine Reports
Gizem Ölmezer, Maryna Levikova, Dominique Klein, Benoît Falquet, Gabriele Alessandro Fontana, Petr Cejka, Ulrich Rass
Cells have evolved mechanisms to protect, restart and repair perturbed replication forks, allowing full genome duplication, even under replication stress. Interrogating the interplay between nuclease-helicase Dna2 and Holliday junction (HJ) resolvase Yen1, we find the Dna2 helicase activity acts parallel to homologous recombination (HR) in promoting DNA replication and chromosome detachment at mitosis after replication fork stalling. Yen1, but not the HJ resolvases Slx1-Slx4 and Mus81-Mms4, safeguards chromosome segregation by removing replication intermediates that escape Dna2...
October 25, 2016: Nature Communications
Biljana Stojković, Ahmed Sayadi, Mirko Đorđević, Jelena Jović, Uroš Savković, Göran Arnqvist
Mitochondria play a key role in ageing. The pursuit of genes that regulate variation in lifespan and ageing have shown that several nuclear-encoded mitochondrial genes are important. However, the role of mitochondrial-encoded genes (mtDNA) is more controversial and our appreciation of the role of mtDNA for the evolution of lifespan is limited. We use replicated lines of seed beetles that have been artificially selected for long or short life for >190 generations, now showing dramatic phenotypic differences, to test for a possible role of mtDNA in the divergent evolution of ageing and lifespan...
October 25, 2016: Evolution; International Journal of Organic Evolution
Koji Shimozaki
Adult neurogenesis originates from neural stem cells (NSCs) in specific regions of the adult brain. The molecular mechanisms that control the self-renewal and multipotency of NSCs have not been fully elucidated. In recent years, emerging evidence has revealed that ten-eleven translocation (TET) family DNA dioxygenases TET1 and TET2 play important roles in the central nervous system. Here, I present evidence that Tet1 and Tet2 are expressed in cultured NSCs derived from adult mouse brain and play an important role in the proliferative self-renewal of NSCs in an undifferentiated state...
October 24, 2016: Cellular and Molecular Neurobiology
Abolfazl Avan, Ravi Narayan, Elisa Giovannetti, Godefridus J Peters
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B...
October 10, 2016: World Journal of Clinical Oncology
Lianghua Bin, Donald Y M Leung
BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory disease caused by the complex interaction of genetic, immune and environmental factors. There have many recent discoveries involving the genetic and epigenetic studies of AD. METHODS: A retrospective PubMed search was carried out from June 2009 to June 2016 using the terms "atopic dermatitis", "association", "eczema", "gene", "polymorphism", "mutation", "variant", "genome wide association study", "microarray" "gene profiling", "RNA sequencing", "epigenetics" and "microRNA"...
2016: Allergy, Asthma, and Clinical Immunology
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