Mechanisms of trinucleotide repeat instability during human development

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Abstract
Trinucleotide expansion in human disease occurs at different stages and in different cell types during development. The status of cell division determines the mechanism of expansion. Large expansions occur in non-dividing cells. Large repeat tracts are deleted in spermatogonia. Pre-mutation alleles can expand or contract in dividing and non-dividing cells. In non-dividing cells, expansion is likely to occur during excision repair. Candidate pathways are base excision repair or transcription-coupled repair. Oxidative damage of DNA bases is corrected by base excision repair and expansion occurs during the process of removing oxidized bases. Loss of 7,8-dihydro-8-oxoguanine DNA glycosylase (OGG1, also known as N-glycosylase/DNA lyase) in mice suppresses expansion. Cockayne syndrome protein CSB (also known as ERCC6) and xeroderma pigmentosum complementation group G (XPG) have been implicated in instability of CAG repeats in flies and in human cells. In dividing cells, replication dependent repair mechanisms, such as polymerase 'back-up' and trans-lesion synthesis, are candidates for causing expansion. Expansion is a two-step process in which DNA loops are formed and then incorporated into DNA. The two steps may occur by distinct mechanisms. The mismatch repair system may be involved in forming the DNA loops that become expansions and may also be involved in loop incorporation into DNA. Progress in this field will require the integration of various strategies, including genetic and biochemical methods and analysis of DNA repair crosstalk and chromatin dynamics.