Browsing by Author "Mair, Nicola"

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    Age-induced errors in DNA replication and repair in Saccharomyces cerevisiae
    (2023-01-17) Mair, Nicola; Cobb, Jennifer; Goodarzi, Aaron; Williams, Gareth; Schriemer, David
    Aging is a multifactor process that leads to a widespread decrease in cellular function. The single most significant risk factor for developing cancer is age. Cancer is a disease of genome instability, and much of this genomic damage accumulates during DNA replication and inefficient repair. Although DNA replication and repair mechanisms have been extensively studied, little is known about whether these processes are altered with age. Accordingly, my thesis aims to define age-related differences in DNA replication and repair in the model organism budding yeast (Saccharomyces cerevisiae). By employing budding yeast as a model system, I have developed a protocol to isolate large quantities of precisely aged cells, thus allowing molecular comparisons between young and old cells. The results indicate that during cellular aging, there is a reduction in the efficiency of replication initiation. There is a reduction in the recruitment of polymerases and MCM helicases to the origins of replication. This coincides with a decrease in origin firing and DNA synthesis. I have also shown that double-strand break (DSB) repair becomes highly mutagenic as yeast cells age. The efficiency of homologous recombination and non-homologous end joining decreases, and the incidence of repair through alternative end-joining increases. Aged cells have an overall lower level of repair, and the recruitment of repair proteins to DSBs is impaired. Altogether, my work has identified mechanisms of DNA replication and repair that become increasingly dysregulated with age.