Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 302, Issue 5, Pages 1063-1080Publisher
ACADEMIC PRESS LTD
DOI: 10.1006/jmbi.2000.4073
Keywords
Friedreich's ataxia; trinucleotide repeat; parallel-stranded DNA; tripler; NMR
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Funding
- NIGMS NIH HHS [R01GM54652] Funding Source: Medline
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The onset and progress of Friedreich's ataxia (FRDA) is associated with the genetic instability of the (GAA).(TTC) trinucleotide repeats located within the frataxin gene. The instability of these repeats may involve the formation of an alternative DNA structure. Poly-purine (R)/poly-pyrimi dine (Y) sequences typically form tripler DNA structures which may contribute to genetic instability. Conventional wisdom suggested that tripler structures formed by these poly-purine (R)/poly-pyrimidine (Y) sequences may contribute to their genetic instability. Here, we report the characterization of the single-stranded GAA and TTC sequences and their mixtures using NMR, W-melting, and gel electrophoresis, as well as chemical and enzymatic probing methods. We show that the FRDA GAA/TTC, repeats are capable of forming various alternative structures. The most intriguing is the observation of a parallel (GAA).(TTC) duplex in equilibrium with the antiparallel Watsori-Crick (GAA).(TTC) duplex. We also show that the GAA strands form self-assembled structures, whereas the TTC strands are essentially unstructured. Finally, we demonstrate that the FRDA repeats form only the YRY triplex (but not the RRY tripler) at neutral pH and the complete formation of the YRY tripler requires the ratio of GAA to TTC strand larger than 1:2. The structural features presented here and in other studies distinguish the FRDA (GAA).(TTC) repeats from the fragile X (CGG).(CCG), myotonic dystrophy (CTG).(CAG) and the Huntington (CAG).(CTG) repeats. (C) 2000 Academic Press.
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