The long-term objectives of this research are to identify and study the different genetic pathways used by cells to avoid DNA damage. DNA damage is corrected by repair and recombination pathways. The components of these pathways and how they are regulated will be studied. Of particular interest are the recombination events that occur between repeated sequences as these can lead to genome rearrangements, many of which are found in human diseases involving neoplastic cells. Deletions between direct repeats may be one mechanism for loss of heterozygousity (LOH). LOH events are the prime metagenetic event in many cancers. There are three main areas of investigation that are proposed: 1) study of the mitotic pathways that result in spontaneous deletions between direct repeats; 2) study of the hpr1-mediated direct repeat deletion pathway and its relationship to transcription; and 3) study of an interhomolog-specific mitotic recombination pathway. To address these problems the following specific aims are proposed: 1) studies on the role of transcription in hyper-recombination mutants, using recombination systems that are stimulated by transcription; 2) study of the SOH9 gene and its human homolog in yeast; 3) examination of the substrate for hpr1-mediated events; 4) examination of the cause of plasmid instability in hpr1 mutants; 5) characterization of DNA binding activities of the Hpr1 protein; and 6) study of the interhomolog-specific mitotic recombination pathway.
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