Mechanisms of Chromosome Breakage and Rearrangements Induced by Repeats that Adopt DNA Secondary Structures

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

Mechanisms of Chromosome Breakage and Rearrangements Induced by Repeats that Adopt DNA Secondary Structures Chromosomes of many eukaryotic organisms including humans contain a large number of repetitive sequences. Several types of commonly present DNA repeats can be arranged in sequence motifs which are able to adopt hairpin and cruciform secondary structures. Inverted repeats, AT- and GC-rich micro- and minisatellites comprising this class of sequence motifs are frequently found in chromosomal regions that are prone to gross rearrangements such as translocations, deletions, inversions and amplifications. Recent studies indicate that a double-strand break (DSB) occurring at the sites of the inverted repeats (IRs) and long tracks of CTG/CAG triplet repeats can be an initial event in generation of chromosome rearrangements. However, little is currently known about the mechanisms underlying this type of genetic instability. The overall goal of this study is to understand the mechanisms by which repeats that have potential to form hairpins and cruciforms can initiate DSB's and subsequent chromosome aberrations. The study will be done using a newly developed model system in the yeast Saccharomyces cerevisiae. The specific objectives are (1) to determine the molecular mechanisms by which hairpin- or cruciform-associated DSB's lead to gross chromosomal rearrangements; and (2) to identify genetic pathways that contribute to DSB formation at the sites of unstable repeats. The information obtained as a result of this research will improve the knowledge of molecular events responsible for chromosome instability. The research heavily relies on the active participation of undergraduate and graduate students. The research team carrying out this study is expected to include female researchers and minorities, who will be recruited from the student population at Georgia Institute of Technology.