Margaret J. Kovach, PhD

….It is our hypothesis that the accumulation of these variants through defects in mismatch repair or the normal aging process contribute to cancer progression by influencing gene expression and chromatin remodeling as it relates to the positioning of regulatory elements, mRNA stability and methylation status of CpG islands (Figure 1).  We propose that microsatellite repeat elements represent a normal, but as yet uncharacterized, mechanism of gene regulation in which polymorphisms in microsatellite repeats function to control the local secondary structure of the genome and mRNA transcripts.  We predict that microsatellite allelic variants (polymorphic for the number of repeat units) generate alternate secondary structures that are important in the recruitment and binding of transcriptional accessory and processing proteins that directly influence the rate of transcription and transcript stability. We also predict that a relationship exists between the local DNA structure induced by microsatellite variability and the methylation status of CpG islands, presenting an indirect mechanism by which microsatellite repeat elements may influence transcription through chromatin remodeling.