DNA repair and trinucleotide repeat instability.
enes harboring certain trinucleotide repeat (TNR) sequences are at risk for high-frequency mutations that expand or contract the repeat tract. The triplet sequences CNG (where N = any nucleotide) and GAA are known to cause human disease when they expand by more than a few repeats in certain key genes. One of the crucial questions in the field is the mechanism (or, more likely, mechanisms) of triplet repeat expansions and contractions. The available evidence indicates that TNRs can change length as a result of aberrant DNA replication in proliferating cells. In addition, TNR instability can arise from gene conversion or by error-prone DNA repair whether the cell is dividing or not, since most cell types have recombination and repair activities. The latter of these three sources, DNA repair, is the subject of this review because of some recent provocative findings. Two non-mutually exclusive views of DNA repair and TNR instability predominate at this time. One idea is that aberrant DNA structure within TNRs blocks repair. Thus even cells with normal repair activities are inhibited from preventing expansions or contractions, due to local DNA structures formed by TNR sequences. A pernicious second model is that DNA repair actually contributes to TNR instability. This idea of pro-mutagenic DNA repair, although seemingly counterintuitive, has support from a number of studies. A simple explanation is that repair is triggered either by DNA damage in or near the TNR, or perhaps by the aberrant TNR-DNA structure itself. Subsequent excision of nucleotides is followed by error-prone repair synthesis. The idea that repair synthesis is a culprit in expansions or contractions ties into the established ideafz that DNA replication through TNRs gives rise to instability. Since DNA synthesis also occurs during gene conversion, a common source of TNR instability could well be the errors that arise when DNA polymerases attempt to synthesize the problematic triplet repeat sequence.
Lahue
Robert S
RS
Eppley Institute for Research in Cancer and Allied Diseases, and Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA. rlahue@unmc.edu
Slater
Danielle L
DL
D000818:Animals; D004260:DNA Repair / Q000502:physiology*; D006801:Humans; D019680:Trinucleotide Repeat Expansion / Q000502:physiology*