Influence of Retrotransposition on DNA Damage and Repair in Aging Cells

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The immediate research goal of this project is to determine the potential contribution of retrotransposons, a class of mobile genetic elements, to increases in frequencies of mutations and chromosome rearrangements that occur during aging. A broader objective is to build upon research, training, and interactions with the scientific community during the mentored phase of the project to develop an independent research program to investigate the consequences of changes in genome instability for aging and how retrotransposons influence genome instability. Yeast will be used as an experimental organism to more efficiently address the aims ofthe project. Yeast and human aging are controlled by related genetic pathways and are characterized by increases in frequencies of genetic damage. Furthermore, yeast and human retrotransposons can contribute to the same kinds of genetic changes. Modulation of the activity of endogenous yeast retrotransposons through mutations, use of different genetic backgrounds, and changes in growth media will be combined with genetic systems to select or screen for mutations and chromosome rearrangements in aging cells. Molecular analyses, including DNA sequencing and DNA microarrays, will then be used to examine mutation spectra and characterize chromosome rearrangements. Mutant strains with deficiencies in specific DNA repair processes will also be used to investigate the relationship between lifespan and particular forms of genome instability when retrotransposons are active. The work will identify whether retrotransposons contribute to aging-associated genome instability in yeast and whether they are likely to be a good target for interventions to reduce mutations and genome rearrangements during human aging. Such interventions could potentially reduce the loss of tissue/organ function with age and the risk of aging-related diseases. Research materials and systems developed during the mentored phase, core facilities and other resources at the sponsoring institution, and advice from the mentors for the prior phase of the project will all contribute to the development of a distinct independent research program.