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genome stability

Siddhant Bhoir, Althaf Shaik, Vijay Thiruvenkatam, Sivapriya Kirubakaran
Human Tousled-like kinases (TLKs) are highly conserved serine/threonine protein kinases responsible for cell proliferation, DNA repair, and genome surveillance. Their possible involvement in cancer via efficient DNA repair mechanisms have made them clinically relevant molecular targets for anticancer therapy. Innovative approaches in chemical biology have played a key role in validating the importance of kinases as molecular targets. However, the detailed understanding of the protein structure and the mechanisms of protein-drug interaction through biochemical and biophysical techniques demands a method for the production of an active protein of exceptional stability and purity on a large scale...
March 19, 2018: Scientific Reports
Chantal Beatrice Magne Nde, Gloria Casas Gimeno, Maria Docanto, Kevin C Knower, Morag J Young, Jakob Buehn, Edris Sayed, Colin D Clyne
Activation of oestrogen receptor α (ERα) stimulates cell division and tumour growth by modulating the expression of ERα target genes. This activation involves the recruitment of specific proteins with activities that are still not fully understood. Timeless, the human homologue of the Drosophila gene involved in circadian rhythm, was previously shown to be a strong predictor of tamoxifen relapse, and is involved in genomic stability and cell cycle control. In this study, we investigated the interplay between Timeless and ERα, and showed that human Timeless is an ERα coactivator...
March 16, 2018: Journal of Molecular Biology
Stephen J Fletcher, Mikael Boden, Neena Mitter, Bernard J Carroll
Summary: Small RNAs play key roles in gene regulation, defense against viral pathogens and maintenance of genome stability, though many aspects of their biogenesis and function remain to be elucidated. SCRAM (Small Complementary RNA Mapper) is a novel, simple-to-use short read aligner and visualization suite that enhances exploration of small RNA datasets. Availability: The SCRAM pipeline is implemented in Go and Python, and is freely available under MIT license...
March 15, 2018: Bioinformatics
Francois Tardieu, Thierry Simonneau, Bertrand Muller
Drought tolerance involves mechanisms operating at different spatial and temporal scales, from rapid stomatal closure to maintenance of crop yield. We review how short-term mechanisms are controlled for stabilizing shoot water potential and how long-term processes have been constrained by evolution or breeding to fit into acclimation strategies for specific drought scenarios. These short- or long-term feedback processes participate in trade-offs between carbon accumulation and the risk of deleterious soil water depletion...
March 19, 2018: Annual Review of Plant Biology
Thomas H Segall-Shapiro, Eduardo D Sontag, Christopher A Voigt
The internal environment of growing cells is variable and dynamic, making it difficult to introduce reliable parts, such as promoters, for genetic engineering. Here, we applied control-theoretic ideas to design promoters that maintained constant levels of expression at any copy number. Theory predicts that independence to copy number can be achieved by using an incoherent feedforward loop (iFFL) if the negative regulation is perfectly non-cooperative. We engineered iFFLs into Escherichia coli promoters using transcription-activator-like effectors (TALEs)...
March 19, 2018: Nature Biotechnology
Pei-Hua Li, Lin Wang, Yao-Jie Pan, Miao-Miao Sang, Jun-Nian Zheng, Dong-Sheng Pei
c-Jun activation domain-binding protein-1 (Jab1) is a multifunctional protein involved in cell proliferation and apoptosis, DNA damage and repair and genome stability. In a number of types of human carcinoma, the abnormal expression of Jab1 is associated with poor prognosis, suggesting that Jab1 serves a vital function in tumorigenesis. However, the functional effects and the underlying molecular mechanisms of Jab1 in laryngeal squamous cell carcinoma (LSCC) progression remain poorly understood. The results of the present study demonstrate that downregulating Jab1 expression promotes LSCC apoptosis while inhibiting the proliferation of LSCC cells...
April 2018: Oncology Letters
Zhen Zhang, Hongwei Sun, Yu Chen, Tianqi Cao, Zhou Songyang, Junjiu Huang, Yan Huang
About 70% of zebrafish (Danio rerio) genes are orthologues of the human's, which are of great interests, but still largely unknown for their functions. Recently, a report on human histone PARylation factor 1 (HPF1/C4orf27) showed that it is involved in DNA damage response along with poly (ADP-ribose) polymerase 1 (PARP1). However, its function in living organism remains unclear. Given that zebrafish has showed its values in modeling human diseases and physiology, we characterized a zebrafish homolog of human HPF1 by sequence alignment...
March 17, 2018: Development Genes and Evolution
Antoine Molaro, Janet M Young, Harmit S Malik
Eukaryotic genomes must accomplish both compact packaging for genome stability and inheritance, as well as accessibility for gene expression. They do so using post-translational modifications of four ancient canonical histone proteins (H2A, H2B, H3, and H4) and by deploying histone variants with specialized chromatin functions. Some histone variants are conserved across all eukaryotes, whereas others are lineage-specific. Here, we performed detailed phylogenomic analyses of "short H2A histone" variants found in mammalian genomes...
March 16, 2018: Genome Research
Veronika Dill, Bernd Hoffmann, Aline Zimmer, Martin Beer, Michael Eschbaumer
BACKGROUND: Suspension culture of BHK cells allows large-scale virus propagation and cost-efficient vaccine production, while the shift to animal-component-free cell culture media without serum is beneficial for the quality and downstream processing of the product. Foot-and-mouth disease virus is still endemic in many parts of the world and high-quality vaccines are essential for the eradication of this highly contagious and economically devastating disease. METHODS: Changes to the viral genome sequence during passaging in an adherent and a suspension cell culture system were compared and the impact of amino acid substitutions on receptor tropism, antigenicity and particle stability was examined...
March 16, 2018: Virology Journal
Julia K Nussbacher, Gene W Yeo
RNA binding proteins (RBPs) interact with primary, precursor, and mature microRNAs (miRs) to influence mature miR levels, which in turn affect critical aspects of human development and disease. To understand how RBPs contribute to miR biogenesis, we analyzed human enhanced UV crosslinking followed by immunoprecipitation (eCLIP) datasets for 126 RBPs to discover miR-encoding genomic loci that are statistically enriched for RBP binding. We find that 92% of RBPs interact directly with at least one miR locus, and that some interactions are cell line specific despite expression of the miR locus in both cell lines evaluated...
March 15, 2018: Molecular Cell
Amporn Suphatrakul, Thaneeya Duangchinda, Natapong Jupatanakul, Kanjanawadee Prasittisa, Suppachoke Onnome, Jutharat Pengon, Bunpote Siridechadilok
Reporter virus is a versatile tool to visualize and to analyze virus infections. However, for flaviviruses, it is difficult to maintain the inserted reporter genes on the viral genome, limiting its use in several studies that require homogeneous virus particles and several rounds of virus replication. Here, we showed that flanking inserted GFP genes on both sides with ribosome-skipping 2A sequences improved the stability and the consistency of their fluorescent signals for dengue-virus-serotype 2 (DENV2) reporter viruses...
2018: PloS One
Yuval B Simons, Kevin Bullaughey, Richard R Hudson, Guy Sella
Human genome-wide association studies (GWASs) are revealing the genetic architecture of anthropomorphic and biomedical traits, i.e., the frequencies and effect sizes of variants that contribute to heritable variation in a trait. To interpret these findings, we need to understand how genetic architecture is shaped by basic population genetics processes-notably, by mutation, natural selection, and genetic drift. Because many quantitative traits are subject to stabilizing selection and because genetic variation that affects one trait often affects many others, we model the genetic architecture of a focal trait that arises under stabilizing selection in a multidimensional trait space...
March 16, 2018: PLoS Biology
Ramani Baddam, Narender Kumar, Lothar H Wieler, Aditya Kumar Lankapalli, Niyaz Ahmed, Sharon J Peacock, Torsten Semmler
Pyrazinamide (PZA) is an important first-line anti-tuberculosis drug, resistance to which occurs primarily due to mutations in pncA (Rv2043c) that encodes the pyrazinamidase enzyme responsible for conversion of pro-drug PZA into its active form. Previous studies have reported numerous resistance-conferring mutations distributed across the entire length of pncA without any hotspot regions. As different lineages of Mycobacterium tuberculosis display a strong geographic association, we sought to understand whether the genetic background influenced the distribution of mutations in pncA...
March 15, 2018: Scientific Reports
Pingping Jia, Weihang Chai
Genome instability gives rise to cancer. MLH1, commonly known for its important role in mismatch repair (MMR), DNA damage signaling and double-strand break (DSB) repair, safeguards genome stability. Recently we have reported a novel role of MLH1 in preventing aberrant formation of interstitial telomeric sequences (ITSs) at intra-chromosomal regions. Deficiency in MLH1, in particular its N-terminus, leads to an increase of ITSs. Here, we identify that the ATPase activity in the MLH1 N-terminal domain is important for suppressing the formation of ITSs...
March 7, 2018: DNA Repair
Qing Cai, Sen-Miao Tong, Wei Shao, Sheng-Hua Ying, Ming-Guang Feng
Histone acetyltransferases (HATs) and deacetylases (HDACs) maintain dynamics of lysine acetylation/deacetylation on histones and non-histone substrates involved in gene regulation and cellular events. Hos2 is a class I HDAC that deacetylates unique histone H4-K16 site in yeasts. Here, we report that orthologous Hos2 deacetylates H4-K16 and is also involved in the acetylation of histone H3-K56 and the phosphorylation of histone H2A-S129 and cyclin-dependent kinase 1 CDK1-Y15 in Beauveria bassiana, a filamentous fungal insect pathogen...
March 15, 2018: Cellular Microbiology
Lucía Fernández, Alejandra Leivas, Jaime Valentín, Adela Escudero, Dolores Corral, Raquel de Paz, Maria Vela, David Bueno, Rebeca Rodríguez, Juan Manuel Torres, Mariana Díaz-Almirón, Eduardo López-Collazo, Joaquin Martinez-Lopez, Antonio Pérez-Martínez
BACKGROUND: Cancer immunotherapy involving natural killer (NK) cells has gained interest. Here we report two methods to obtain interleukin (IL)-15-activated NK cells for clinical use. STUDY DESIGN AND METHODS: IL-15-activated NK cell products were obtained after 1) enrichment from healthy haploidentical donors' peripheral blood mononuclear cells (PBMNCs) collected by nonmobilized apheresis by a two-step magnetic procedure, depletion of CD3+ cells followed by selection of CD56+ cells and ex vivo overnight stimulation with IL-15 (NKIL15); and 2) expansion using the K562-mb15-41BBL cell line (NKAE), from autologous PBMNCs from patients with multiple myeloma or expansion from healthy haploidentical PBMNCs obtained from whole blood using the same previous cell line...
March 14, 2018: Transfusion
Jinlei Han, Zhiliang Zhang, Kai Wang
It is well known that the chromosomes are organized in the nucleus and this spatial arrangement of genome play a crucial role in gene regulation and genome stability. Different techniques have been developed and applied to uncover the intrinsic mechanism of genome architecture, especially the chromosome conformation capture (3C) and 3C-derived methods. 3C and 3C-derived techniques provide us approaches to perform high-throughput chromatin architecture assays at the genome scale. However, the advantage and disadvantage of current methodologies of C-technologies have not been discussed extensively...
2018: Molecular Cytogenetics
Jonuelle Acosta, Walter Wang, David M Feldser
Tumor suppressor genes play critical roles orchestrating anti-cancer programs that are both context dependent and mechanistically diverse. Beyond canonical tumor suppressive programs that control cell division, cell death, and genome stability, unexpected tumor suppressor gene activities that regulate metabolism, immune surveillance, the epigenetic landscape, and others have recently emerged. This diversity underscores the important roles these genes play in maintaining cellular homeostasis to suppress cancer initiation and progression, but also highlights a tremendous challenge in discerning precise context-specific programs of tumor suppression controlled by a given tumor suppressor...
March 15, 2018: Oncogene
Venkata Rajesh Yella, Aditya Kumar, Manju Bansal
Transcription is an intricate mechanism and is orchestrated at the promoter region. The cognate motifs in the promoters are observed in only a subset of total genes across different domains of life. Hence, sequence-motif based promoter prediction may not be a holistic approach for whole genomes. Conversely, the DNA structural property, duplex stability is a characteristic of promoters and can be used to delineate them from other genomic sequences. In this study, we have used a DNA duplex stability based algorithm 'PromPredict' for promoter prediction in a broad range of eukaryotes, representing various species of yeast, worm, fly, fish, and mammal...
March 14, 2018: Scientific Reports
François Vasseur, Moises Exposito-Alonso, Oscar J Ayala-Garay, George Wang, Brian J Enquist, Denis Vile, Cyrille Violle, Detlef Weigel
Seed plants vary tremendously in size and morphology; however, variation and covariation in plant traits may be governed, at least in part, by universal biophysical laws and biological constants. Metabolic scaling theory (MST) posits that whole-organismal metabolism and growth rate are under stabilizing selection that minimizes the scaling of hydrodynamic resistance and maximizes the scaling of resource uptake. This constrains variation in physiological traits and in the rate of biomass accumulation, so that they can be expressed as mathematical functions of plant size with near-constant allometric scaling exponents across species...
March 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
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