Global ETD Search

1	Treatment of nonspecific DNA-protein contacts and application to the excision mechanism of a unique human DNA glycosylase Rutledge, Lesley R, University of Lethbridge. Faculty of Arts and Science January 2011 (has links) This thesis concentrates on understanding how individual nonspecific DNA–protein contacts are used in the excision mechanism of the human DNA repair enzyme, alkyladenine DNA glycosylase (AAG). Initially, studies focus on understanding the structure and magnitude of these fundamentally different DNA–protein stacking and T-shaped interactions to be applied to the active site of AAG. High-level ab initio techniques revealed fundamental knowledge about the structure and magnitude of these distinctly different – and +– contacts between (one or two) conjugated amino acid(s) and one nucleobase. Additionally, the mechanism used by AAG to excise (neutral and cationic) damaged nucleotides was investigated using a hybrid ONIOM approach. Reaction potential energy surfaces reveal that AAG prefers to excise both neutral and cationic substrates through a concerted mechanism, yet the nonspecific contacts present in the active site are only catalytic for the cleavage of the neutral substrates. / xvi, 195 leaves : ill. (some col.) ; 29 cm + 1 CD-ROM DNA ligases -- Research DNA repair -- Research DNA -- Methylation -- Research Alkylation Glycoproteins -- Research Dissertations, Academic
2	The down-regulation of Ku70, DNA-PKcs, and Parp-1 in mammalian cell lines Wickersham, Stephanie January 2012 (has links) DNA double strand breaks (DSBs) are primarily repaired in eukaryotic cells by two different mechanisms – non-homologous end joining (NHEJ) or homologous recombination (HR). In mammalian somatic cells the balance between the two highly favours NHEJ. Gene targeting is a technique that exploits HR repair to alter a defined gene locus. While it holds potential to be implemented as a treatment option for several diseases, the outlook for using it in a clinical setting has been obstructed by a low gene targeting efficiency. This has been coupled to the low frequency of HR in mammalian cells. With the intention of shifting the repair balance, antibodies against DSB repair proteins will be introduced into mammalian cells. It is predicted that by targeting key repair proteins with antibodies, a compensatory increase in the frequency of HR can be fostered, ultimately resulting in improved gene targeting. / xv, 168 leaves : ill. ; 29 cm DNA damage -- Research DNA repair -- Research Gene targeting -- Research Protein kinases NAD-ADP-ribosyltransferase
3	Role of eIF3a expression in cellular sensitivity to ionizing radiation treatments by regulating synthesis of NHEJ repair proteins Tumia, Rima Ahmed .N. Hashm 11 November 2015 (has links) Indiana University-Purdue University Indianapolis (IUPUI) / Translation Initiation in protein synthesis is a crucial step controlling gene expression that enhanced by eukaryotic translation initiation factors (eIFs). eIF3a, the largest subunit of eIF3 complexes, has been shown to regulate protein synthesis and cellular response to cisplatin treatment. Its expression has also been shown to negatively associate with prognosis. In this study, we tested a hypothesis that eIF3a regulates synthesis of proteins important for repair of double strand DNA breaks induced by ionizing radiation (IR). We found that eIF3a up-regulation sensitizes cellular response to IR while its knockdown causes resistance to IR. We also found that eIF3a over-expression increases IR-induced DNA damage and decreases Non-Homologous End Joining (NHEJ) activity by suppressing expression level of NHEJ repair proteins such as DNA-PKcs and vice versa. Together, we conclude that eIF3a plays an important role in cellular response to DNA-damaging treatments by regulating synthesis of DNA repair proteins and, thus, eIIF3a likely plays an important role in the outcome of cancer patients treated with DNA-damaging strategies including ionizing radiation. DNA repair -- Research Transcription factors -- Research Ionizing radiation -- Research Cancer -- Patients -- Research Genetic translation Cisplatin -- Treatment Proteins -- Synthesis
4	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

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