Human Repetitive DNA Sequences as a Source of Chromosomal Fragility and Genome Rearrangements in Yeast: Implications for Human Polymorphisms and Diseases
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Eukaryotic chromosomes must be accurately maintained, duplicated and segregated during mitotic and meiotic divisions to guarantee inheritance of the correct genetic information by the daughter cells. However, occasionally genome integrity can be compromised: chromosomes break and rearrange which can cause drastic changes in the way how genes are expressed. This type of genetic instability is a causative factor in the development of many hereditary diseases and cancers in humans. On the other hand, the ability of chromosomes to undergo breakage and rearrangements promotes genetic variations that contribute to species polymorphisms and evolution. Multiple environmental and intracellular factors such as ionizing radiation, UV light or reactive oxygen species are well-established damaging agents that can fracture chromosomes at any position and trigger chromosomal abnormalities. Nevertheless, work over recent years has established that breaks along the chromosomes do not occur randomly but rather often coincide with the regions containing repetitive elements capable of adopting non-canonical DNA secondary structures. The enigmatic discovery that DNA repeats which can be inherited or occur de novo are a very powerful source of the breakage and rearrangements adds new perspective to our understanding of the origin of human pathology, polymorphism and evolution. Why breaks happen, what genetic and environmental factors contribute to fragility, what are the consequences of these types of breaks for the integrity of the eukaryotic genome? Those are the questions that we are trying to address using yeast as a model eukaryotic organism in my laboratory. I will present our new findings related to three sequence motifs that can adopt different secondary structures. The underlying mechanisms of repeat-mediated breakage uncovered in yeast can be extrapolated to the studies of chromosomal dynamics of higher eukaryotes including humans.