Expanded CAG Repeats Activate the DNA Damage CheckpointPathway;Structure-Forming CAG/CTG Repeat Sequences Are Sensitive to Breakage in the Absence of Mrc1Checkpoint Function and S-Phase Checkpoint Signalling:Implications for Trinucleotide Repeat Expa

摘要

The repeat expansion diseases are a group of disorders characterized by anincrease in the length of a specific tandem repeat tract. The increase in repeat number hasconsequences that depend both on the sequence of the repeat and its location within the affectedgene(reviewed in Usdin and Grabczyk). The likelihood of expansion is related to the number ofrepeats and their purity,as well as to chromosomal context. The repeats are prone to expansionduring germ-line development or early embryogenesis. In some instances significant instability isalso seen in somatic cells throughout life. Whether the same mechanisms are responsible for bothsomatic and germ-line instability is not clear. In addition,whereas in some cases the increase inrepeat number is fairly modest,in others it is quite extensive. Again it is not clear whether thesame mechanism is responsible for both the small and large tract length changes. In addition tobeing unstable,long CGG centre dot CCG repeat tracts also form folate-sensitive fragile sites inmammalian cells. Fragile sites are frequent points of chromosome breakage in humans,and although CTGcentre dot CAG repeats have not been shown to form fragile sites in mammalian cells,they do have anincreased incidence of chromosome breakage in the budding yeast Saccharomyces cerevisiae.