DNA TRANSACTIONS AND GENOME INTEGRITY IN AGING

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This proposal includes a set of six research projects which form a coherent and integrated effort to understand the processes tending to alter genome structure and organization, and the mechanisms cells possess to promote, resist and repair such modifications. Because these processes are undoubtedly fundamental to cell and organismal survival, we presume that they may be important in cellular and organismal senescence. Accordingly, a principal aim of this program project is to characterize the participants and molecular mechanisms of selected DNA transactions, and to explore their status and possible relevance to the aging process. The individual projects focus on: 1. repair of double strand breaks and deletions by recombination in mammalian cells, 2. regulation of chromosomal replication and its influence on the frequency of chromosome breakage, recombinational loss and nondisjunction, 3. an assessment of the role of DNA damage and repair in aging phenomena by studies of the developmental or age-related factors which account for the variation in the repairability of DNA damage in different regions of the genome of terminally differentiated cells, 4. an analysis of the replication and error-correction processes in highly purified replication systems with a view toward establishing assays and criteria for evaluating replication fidelity during aging processes, 5. factors governing genome integrity: the replication fidelity of normal and damaged DNA by Herpes Simplex DNA polymerase, and the mechanism of site-specific intramolecular recombination between homologous sequences catalyzed by a recently detected mammalian enzyme, 6. the mechanism of genome rearrangements leading to the assembly of functional immunoglobin heavy and light chains, particularly the switch recombinations that link a heavy chain variable region to any one of five constant regions.