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221	Cascades of genetic instability resulting from compromised break-induced replication Vasan, Soumini January 2013 (has links) Indiana University-Purdue University Indianapolis (IUPUI) / Break-induced replication (BIR) is a mechanism to repair double-strand breaks (DSBs) that possess only a single end that can find homology in the genome. This situation can result from the collapse of replication forks or telomere erosion. BIR frequently produces various genetic instabilities including mutations, loss of heterozygosity, deletions, duplications, and template switching that can result in copy-number variations (CNVs). An important type of genomic rearrangement specifically linked to BIR is half crossovers (HCs), which result from fusions between parts of recombining chromosomes. Because HC formation produces a fused molecule as well as a broken chromosome fragment, these events could be highly destabilizing. Here I demonstrate that HC formation results from the interruption of BIR caused by a defective replisome or premature onset of mitosis. Additionally, I document the existence of half crossover instability cascades (HCC) that resemble cycles of non-reciprocal translocations (NRTs) previously described in human tumors. I postulate that HCs represent a potent source of genetic destabilization with significant consequences that mimic those observed in human diseases, including cancer. Comparative Genomic Hybridization Break-induced Replication Copy Number Variations Chromosomal Rearrangements Double-strand Break Repair Half Crossover Homologous Recombination Non-reciprocal Translocation Half crossover instability cascades DNA double-strand break DNA repair Genetic instabilities Array-CGH DNA repair -- Research -- Analysis DNA damage -- Research -- Analysis DNA microarrays -- Research -- Analysis DNA replication -- Regulation DNA -- Analysis Genetic recombination -- Research Mutagenesis -- Research Molecular biology -- Research Mitosis -- Regulation -- Research DNA polymerases DNA -- Synthesis Tumors -- Genetic aspects Cancer -- Genetic aspects
222	Stabil och antibiotikafri läkemedelsproduktion i rekombinant Escherichia coli Benevides, Kristina, Broström, Oscar, Elison Kalman, Grim, Swenson, Hugo, Vlassov, Andrei, Ågren, Josefin January 2017 (has links) Den här rapporten presenterar ett antibiotikafritt, stabilt och kromosombaserat expressionssystem för läkemedelsproduktion i Escherichia coli på beställning av företaget Affibody AB. E. coli-stammen BL21(DE3) valdes som värdorganism för expressionssystemet. Systemet består av en genkassett som innehåller en T7-promotor, en 5′-UTR från genen ompA och en terminatorsekvens från RNA-operonet rrnB. Fyra kopior av genkassetten ska integreras i pseudogenerna caiB, yjjM, hsdS och yjiV. En datormodell som modellerar det egentliga kopietalet i cellerna har skapats i mjukvaran MATLAB, vilket visar att det uppskattas vara maximalt 32 kopior av genkassetten per cell på grund av replikation av kromosomen. Ett högt pH i fermentorn; att använda fed-batch och blandade kolhydratkällor; och att använda stammen BL21(DE3) minskar acetatproduktionen i cellen. En lägre acetatproduktion kan leda till en högre produkthalt. En proteinutbytesmodell för mjukvaran MATLAB har konstruerats för att uppskatta koncentrationen av Affibody®-molekylen i en E. coli cell. copynumber copy-number copy number origin of replication rekombinant proteinexpression läkemedel E. coli antibiotikafri antibiotika expressionssystem expression system escherichia coli kromosom kromosombaserad kromosomal plasmidfri plasmid T7-promotor T7 promotor ompA rrnB autoinduktion auto induktion matlab kopietalmodell utbytemodell stabil pH pseudogen pseudo gen caiB yjjM hsdS yjiV fermentor batch fed-batch kontinuerlig fed batch fermentation Affibody affibody-molekyl affibody-molekyler affibodymolekyl affibodymolekyler bioreaktor acetat acetatbildning acetatproduktion acetatreduktion acetatreducering peptidläkemedel peptider peptid T7-system operator lac-operator operon 5'-UTR 3'-UTR sekundärstruktur mRNA T1 T2 terminator termineringssekvens optimering lac-operon repressor inducering BL21(DE3) BL21 B-stam B stam modell kopietal kopie tal OriC Pharmaceutical Biotechnology Läkemedelsbioteknik

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Cascades of genetic instability resulting from compromised break-induced replication

Stabil och antibiotikafri läkemedelsproduktion i rekombinant Escherichia coli