Mechanisms of Chromosomal Fragility and Rearrangements Triggered by Human Unstable Repeats
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Research of my lab focuses on understanding how chromosomal rearrangements arise and lead to hereditary diseases and cancer. Chromosomes containing repeats that can adopt stable secondary structures are highly prone for double-strand breaks and various types of rearrangements. Molecular mechanisms for this type of genetic instability in eukaryotes are poorly understood. Using yeast, S. cerevisiae, we are investigating the chromosomal fragility mediated by two sequence motifs: cruciform-forming inverted repeats and H-DNA-forming GAA/TTC triplet repeats. Both types of repeats strongly induce breakage which results from the replication arrest by the secondary structures. However, genetic requirements for fragility, mode of breakage and consequences for the genome integrity are different for these two types of repeats. We propose that the nature of the secondary structure predisposes chromosomes for the specific pattern of gross chromosomal rearrangements. These rearrangements are strikingly similar to carcinogenic aberration suggesting that repeat-mediated instability might be a general phenomenon that operates not only in yeast but also in humans. I will present recent data from my lab on proteins that are involved into the fragility.