Minisatellites in meiosis: crossover regulation and stability of repetitive DNA.

Abstract

The minisatellite associated with the human HRAS1 proto-oncogene has an enhancer effect on HRAS1 expression. Rare minisatellite alleles have stronger enhancer activity and are frequently found in primary tumors of cancer patients. Rare alleles derive from a common allele that has undergone an alteration in length; alterations occur primarily during the process of meiotic recombination. Identifying factors that regulate minisatellite stability during meiosis is important to our understanding of the initiation and predisposition of minisatellite-associated human diseases. This is the focus of the Kirkpatrick lab using a minisatellite model system in yeast Saccharomyces cerevisiae where an HRAS1 minisatellite allele has been inserted into the promoter region upstream of the HIS4 locus on chromosome III. In this study, we identified CSM3, TOF1, and MRC1 as factors that contribute to meiotic minisatellite alterations. We also uncovered a novel recombination phenotype associated with the HRAS1 minisatellite in MSH4 and MSH5 mutants. Both of these projects have broader implications on our understanding of factors that regulate minisatellite alterations during meiosis. We present models based on our data and previously published research to explain the observed phenotypes.