| Popis: |
Disease-associated repeat instability can occur in various patient tissues, including germ cells, proliferating somatic tissues, and nonproliferating tissues like the brain. Various DNA metabolic processes could potentially give rise to slipped DNAs at the repeats—the supposed mutagenic intermediate of repeat instability. Transgenic mice with (CTG)·(CAG) repeats have revealed a requirement for several mismatch repair genes for the spontaneous expansion of the repeats. Results with an in vitro repair assay using human cell extracts and structurally defined slipped DNAs have revealed several distinct repair outcomes: correct repair, escaped repair, and error-prone repair, some of which can give rise to the expansion bias occurring in patients. These processes can be mediated by neuron-like cells supporting their contribution to instability in patient brains. Notably, the mismatch and nucleotide excision repair proteins such as hMSH2, hMSH3, hMLHl, XPF, or XPG were not involved in processing of the slip outs. This suggests that, if these proteins are involved in expansion, their role precedes the step of slip-out processing. |
