Chemotherapeutically induced deletion of expanded triplet repeats.
The number of neurodegenerative disorders associated with the expansion of DNA repeats, currently about 18, continues to increase as additional diseases caused by this novel type of mutation are identified. Typically, expanded repeats are biased toward further expansion upon intergenerational transmission, and disease symptoms show an earlier age of onset and greater severity as the length of the triplet repeat tract increases. Most diseases exhibit progressive neurological and/or muscular degeneration that can lead to total disability and death. As yet, no treatment exists for the genetic basis of any repeat disease. Given that the severity of these diseases is related to repeat tract length, reducing repeat lengths might delay the onset and reduce disease severity. Here, we test the hypothesis that the introduction of damage into DNA, which results in subsequent repair events, can lead to an increased rate of repeat deletion. Applying a sensitive genetic assay in Escherichia coli [Mut. Res. 502 (2002) 25], we demonstrate that certain DNA damaging agents, including EMS, ENU, UV light, and anticancer agents mitomycin C, cisplatin, and X-rays increase the rate of deletion of (CTG).(CAG) repeats in a length and orientation dependent fashion. In addition, oxidative damage to DNA also increases the deletion rate of repeats. These results suggest that a chemotherapeutic approach to the reduction in triplet repeat length may provide one possible rationale to slow, stop, or reverse the progression of these diseases.
Hashem
Vera I
VI
Laboratory of DNA Structure and Mutagenesis, Center for Genome Research, Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 West Holcombe Blvd, Houston, TX 77030-3303, USA.
Sinden
Richard R
RR
D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000009:adverse effects; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D003609:Dactinomycin / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D005020:Ethyl Methanesulfonate / Q000633:toxicity; D005038:Ethylnitrosourea / Q000633:toxicity; D016685:Mitomycin / Q000009:adverse effects; D009153:Mutagens / Q000633:toxicity*; D018384:Oxidative Stress; D010957:Plasmids / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D017384:Sequence Deletion; D018911:Trinucleotide Repeats / Q000187:drug effects* / Q000528:radiation effects; D014466:Ultraviolet Rays; D014965:X-Rays
D000970:Antineoplastic Agents; D009153:Mutagens; D003609:Dactinomycin; D016685:Mitomycin; D005020:Ethyl Methanesulfonate; D005038:Ethylnitrosourea; D002945:Cisplatin