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Synthetic genetics

Alexander I Taylor, Philipp Holliger
This unit describes the application of "synthetic genetics," i.e., the replication of xeno nucleic acids (XNAs), artificial analogs of DNA and RNA bearing alternative backbone or sugar congeners, to the directed evolution of synthetic oligonucleotide ligands (XNA aptamers) specific for target proteins or nucleic acid motifs, using a cross-chemistry selective exponential enrichment (X-SELEX) approach. Protocols are described for synthesis of diverse-sequence XNA repertoires (typically 1014 molecules) using DNA templates, isolation and panning for functional XNA sequences using targets immobilized on solid phase or gel shift induced by target binding in solution, and XNA reverse transcription to allow cDNA amplification or sequencing...
June 2018: Current Protocols in Chemical Biology
Anssi Rantasalo, Christopher P Landowski, Joosu Kuivanen, Annakarin Korppoo, Lauri Reuter, Outi Koivistoinen, Mari Valkonen, Merja Penttilä, Jussi Jäntti, Dominik Mojzita
Biotechnological production of fuels, chemicals and proteins is dependent on efficient production systems, typically genetically engineered microorganisms. New genome editing methods are making it increasingly easy to introduce new genes and functionalities in a broad range of organisms. However, engineering of all these organisms is hampered by the lack of suitable gene expression tools. Here, we describe a synthetic expression system (SES) that is functional in a broad spectrum of fungal species without the need for host-dependent optimization...
June 19, 2018: Nucleic Acids Research
Leonard Katz, Yvonne Y Chen, Ramon Gonzalez, Todd C Peterson, Huimin Zhao, Richard H Baltz
Synthetic biology is a logical extension of what has been called recombinant DNA (rDNA) technology or genetic engineering since the 1970s. As rDNA technology has been the driver for the development of a thriving biotechnology industry today, starting with the commercialization of biosynthetic human insulin in the early 1980s, synthetic biology has the potential to take the industry to new heights in the coming years. Synthetic biology advances have been driven by dramatic cost reductions in DNA sequencing and DNA synthesis; by the development of sophisticated tools for genome editing, such as CRISPR/Cas9; and by advances in informatics, computational tools, and infrastructure to facilitate and scale analysis and design...
June 18, 2018: Journal of Industrial Microbiology & Biotechnology
Rachel Brough, Aditi Gulati, Syed Haider, Rahul Kumar, James Campbell, Erik Knudsen, Stephen J Pettitt, Colm J Ryan, Christopher J Lord
Although defects in the RB1 tumour suppressor are one of the more common driver alterations found in triple-negative breast cancer (TNBC), therapeutic approaches that exploit this have not been identified. By integrating molecular profiling data with data from multiple genetic perturbation screens, we identified candidate synthetic lethal (SL) interactions associated with RB1 defects in TNBC. We refined this analysis by identifying the highly penetrant effects, reasoning that these would be more robust in the face of molecular heterogeneity and would represent more promising therapeutic targets...
June 18, 2018: Oncogene
Melissa Tumen-Velasquez, Christopher W Johnson, Alaa Ahmed, Graham Dominick, Emily M Fulk, Payal Khanna, Sarah A Lee, Alicia L Schmidt, Jeffrey G Linger, Mark A Eiteman, Gregg T Beckham, Ellen L Neidle
Experimental evolution is a critical tool in many disciplines, including metabolic engineering and synthetic biology. However, current methods rely on the chance occurrence of a key step that can dramatically accelerate evolution in natural systems, namely increased gene dosage. Our studies sought to induce the targeted amplification of chromosomal segments to facilitate rapid evolution. Since increased gene dosage confers novel phenotypes and genetic redundancy, we developed a method, Evolution by Amplification and Synthetic Biology (EASy), to create tandem arrays of chromosomal regions...
June 18, 2018: Proceedings of the National Academy of Sciences of the United States of America
Francisco Marco-Jiménez, Manuel Baselga, José Salvador Vicente
Genetic resource banks (GRB) are a valuable tool for maintaining genetic variability and preserving breeds from pathogens or catastrophe, enabling us to assess and correct breeding schemes, minimizing the impact of genetic drift and facilitating diffusion. This study tests their efficiency in re-establishing two extinct populations of a synthetic rabbit line selected for daily weight gain, using vitrified embryos from two generations (18th and 36th) separated by 15 years of genetic selection. The effect of long-term storage of vitrified embryos in liquid nitrogen was also evaluated...
2018: PloS One
Alice Marino, Takuya Sakamoto, Xiao-Han Tang, Lorraine J Gudas, Roberto Levi
We previously discovered that oral treatment with AC261066, a synthetic selective agonist for the retinoic acid β2-receptor (RARβ2), decreases oxidative stress in the liver, pancreas, and kidney of mice fed a high-fat diet (HFD). Since hyperlipidemic states are causally associated with myocardial ischemia and oxidative stress, we have now investigated the effects of AC261066 in an ex-vivo ischemia/reperfusion (I/R) injury model in hearts of two prototypic dysmetabolic mice. We found that a 6-week oral treatment with AC261066 in both genetically hypercholesterolemic (ApoE-/-) and obese (HFD-fed) wild-type mice exerts protective effects when their hearts are subsequently subjected to I/R ex vivo in the absence of added drug...
June 15, 2018: Journal of Pharmacology and Experimental Therapeutics
Alexander C Bertalovitz, Marika L Osterbur Badhey, Thomas V McDonald
Synonymous nucleotide variation is increasingly recognized as a factor than can affect protein expression, but the underlying mechanisms are incompletely understood. Here, we investigated whether synonymous changes could affect expression of the potassium voltage gated channel subfamily H member 2 (KCNH2) gene, encoding the human ether-a-go-go related gene (hERG) ion channel which is linked to hereditary cardiac arrhythmia. We examined a previously described synthetic version (hERG-CM) with synonymous substitutions designed to reduce GC content, rare codons, and mRNA secondary structure relative to the native construct (hERG-NT)...
June 15, 2018: Journal of Biological Chemistry
Agnieszka A Piatek, Scott C Lenaghan, C Neal Stewart
Genome editing is a powerful suite of technologies utilized in basic and applied plant research. Both nuclear and plastid genomes have been genetically engineered to alter traits in plants. While the most frequent molecular outcome of gene editing has been knockouts resulting in a simple deletion of an endogenous protein of interest from the host's proteome, new genes have been added to plant genomes and, in several instances, the sequence of endogenous genes have been targeted for a few coding changes. Targeted plant characteristics for genome editing range from single gene targets for agronomic input traits to metabolic pathways to endow novel plant function...
August 2018: Plant Science: An International Journal of Experimental Plant Biology
Benjamin Pouvreau, Thomas Vanhercke, Surinder Singh
Genetic improvement of crops started since the dawn of agriculture and has continuously evolved in parallel with emerging technological innovations. The use of genome engineering in crop improvement has already revolutionised modern agriculture in less than thirty years. Plant metabolic engineering is still at a development stage and faces several challenges, in particular with the time necessary to develop plant based solutions to bio-industrial demands. However the recent success of several metabolic engineering approaches applied to major crops are encouraging and the emerging field of plant synthetic biology offers new opportunities...
August 2018: Plant Science: An International Journal of Experimental Plant Biology
Tessema K Kassaw, Alberto J Donayre-Torres, Mauricio S Antunes, Kevin J Morey, June I Medford
Plant synthetic biology is a rapidly emerging field that aims to engineer genetic circuits to function in plants with the same reliability and precision as electronic circuits. These circuits can be used to program predictable plant behavior, producing novel traits to improve crop plant productivity, enable biosensors, and serve as platforms to synthesize chemicals and complex biomolecules. Herein we introduce the importance of developing orthogonal plant parts and the need for quantitative part characterization for mathematical modeling of complex circuits...
August 2018: Plant Science: An International Journal of Experimental Plant Biology
L Camesasca, M Minteguiaga, L Fariña, V Salzman, P S Aguilar, C Gaggero, F Carrau
The objective of this work is to demonstrate if the hexaprenyl pyrophosphate synthetase Coq1p might be involved in monoterpenes synthesis in Saccharomyces cerevisiae, although its currently known function in yeast is to catalyze the first step in ubiquinone biosynthesis. However, in a BY4743 laboratory strain, the presence of an empty plasmid in a chemically defined grape juice medium results in a statistically significant increase of linalool, (E)-nerolidol and (E,E)-farnesol. When COQ1 is overexpressed from a plasmid, the levels of the volatile isoprenoids are further increased...
June 6, 2018: International Journal of Food Microbiology
Lihong Jiang, Jiarun Zhao, Jiazhang Lian, Zhinan Xu
Advances in metabolic engineering and synthetic biology have facilitated the manufacturing of many valuable-added compounds and commodity chemicals using microbial cell factories in the past decade. However, due to complexity of cellular metabolism, the optimization of metabolic pathways for maximal production represents a grand challenge and an unavoidable barrier for metabolic engineering. Recently, cell-free protein synthesis system (CFPS) has been emerging as an enabling alternative to address challenges in biomanufacturing...
June 2018: Synthetic and Systems Biotechnology
Swastika Sanyal, Lucia Molnarova, Judita Richterova, Barbora Huraiova, Zsigmond Benko, Silvia Polakova, Ingrid Cipakova, Andrea Sevcovicova, Katarina Gaplovska-Kysela, Karl Mechtler, Lubos Cipak, Juraj Gregan
The canonical role of cohesin is to mediate sister chromatid cohesion. In addition, cohesin plays important roles in processes such as DNA repair and regulation of gene expression. Mounting evidence suggests that various post-translational modifications including phosphorylation, acetylation and SUMOylation regulate cohesin functions. Our mass-spectrometry analysis of cohesin purified from Schizosaccharomyces pombe cells revealed that the cohesin subunit Psm1 is methylated on two evolutionarily conserved lysine residues K536 and K1200...
June 13, 2018: Journal of Cell Science
Eiichi Shoguchi, Girish Beedessee, Ipputa Tada, Kanako Hisata, Takeshi Kawashima, Takeshi Takeuchi, Nana Arakaki, Manabu Fujie, Ryo Koyanagi, Michael C Roy, Masanobu Kawachi, Michio Hidaka, Noriyuki Satoh, Chuya Shinzato
BACKGROUND: The marine dinoflagellate, Symbiodinium, is a well-known photosynthetic partner for coral and other diverse, non-photosynthetic hosts in subtropical and tropical shallows, where it comprises an essential component of marine ecosystems. Using molecular phylogenetics, the genus Symbiodinium has been classified into nine major clades, A-I, and one of the reported differences among phenotypes is their capacity to synthesize mycosporine-like amino acids (MAAs), which absorb UV radiation...
June 14, 2018: BMC Genomics
Carlijn V C Bouten, Anthal I P M Smits, Frank P T Baaijens
In situ heart valve tissue engineering using cell-free synthetic, biodegradable scaffolds is under development as a clinically attractive approach to create living valves right inside the heart of a patient. In this approach, a valve-shaped porous scaffold "implant" is rapidly populated by endogenous cells that initiate neo-tissue formation in pace with scaffold degradation. While this may constitute a cost-effective procedure, compatible with regulatory and clinical standards worldwide, the new technology heavily relies on the development of advanced biomaterials, the processing thereof into (minimally invasive deliverable) scaffolds, and the interaction of such materials with endogenous cells and neo-tissue under hemodynamic conditions...
2018: Frontiers in Cardiovascular Medicine
C R Lindsay, M Jamal-Hanjani, M Forster, F Blackhall
Despite being the most frequent gain-of-function genetic alteration in human cancer, KRAS mutation has to date offered only limited potential as a prognostic and predictive biomarker. Results from the phase III SELECT-1 trial in non-small cell lung cancer (NSCLC) recently added to a number of historical and more contemporary disappointments in targeting KRAS mutant disease, including farnesyl transferase inhibition and synthetic lethality partners such as STK33. This narrative review uses the context of these previous failures to demonstrate how the knowledge gained from these experiences can be used as a platform for exciting advances in NSCLC on the horizon...
June 9, 2018: European Journal of Cancer
Ewa Gogola, Alexandra A Duarte, Julian R de Ruiter, Wouter W Wiegant, Jonas A Schmid, Roebi de Bruijn, Dominic I James, Sergi Guerrero Llobet, Daniel J Vis, Stefano Annunziato, Bram van den Broek, Marco Barazas, Ariena Kersbergen, Marieke van de Ven, Madalena Tarsounas, Donald J Ogilvie, Marcel van Vugt, Lodewyk F A Wessels, Jirina Bartkova, Irina Gromova, Miguel Andújar-Sánchez, Jiri Bartek, Massimo Lopes, Haico van Attikum, Piet Borst, Jos Jonkers, Sven Rottenberg
Inhibitors of poly(ADP-ribose) (PAR) polymerase (PARPi) have recently entered the clinic for the treatment of homologous recombination (HR)-deficient cancers. Despite the success of this approach, drug resistance is a clinical hurdle, and we poorly understand how cancer cells escape the deadly effects of PARPi without restoring the HR pathway. By combining genetic screens with multi-omics analysis of matched PARPi-sensitive and -resistant Brca2-mutated mouse mammary tumors, we identified loss of PAR glycohydrolase (PARG) as a major resistance mechanism...
June 11, 2018: Cancer Cell
Seaim Lwin Aye, Kei Fujiwara, Nobuhide Doi
Engineering and design of genetic circuit in living cell is critical in accessing the beneficial application of synthetic biology. Directed evolution can avoid the complicated rational design of such circuit by screening or selecting functional circuit from non-functional one. Here we proposed a positive-negative selection system for selecting a transcription factor that activates gene expression in response to arsenic in solution. First, we developed a whole cell biosensor for sensing arsenite in liquid using a regulator (ArsR) and a reporter (GFP), and evaluated its performance...
June 8, 2018: Journal of Biochemistry
Yonathan Lissanu Deribe, Yuting Sun, Christopher Terranova, Fatima Khan, Juan Martinez-Ledesma, Jason Gay, Guang Gao, Robert A Mullinax, Tin Khor, Ningping Feng, Yu-Hsi Lin, Chia-Chin Wu, Claudia Reyes, Qian Peng, Frederick Robinson, Akira Inoue, Veena Kochat, Chang-Gong Liu, John M Asara, Cesar Moran, Florian Muller, Jing Wang, Bingliang Fang, Vali Papadimitrakopoulou, Ignacio I Wistuba, Kunal Rai, Joseph Marszalek, P Andrew Futreal
Lung cancer is a devastating disease that remains a top cause of cancer mortality. Despite improvements with targeted and immunotherapies, the majority of patients with lung cancer lack effective therapies, underscoring the need for additional treatment approaches. Genomic studies have identified frequent alterations in components of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A. To understand the mechanisms of tumorigenesis driven by mutations in this complex, we developed a genetically engineered mouse model of lung adenocarcinoma by ablating Smarca4 in the lung epithelium...
June 8, 2018: Nature Medicine
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