Premutation huntingtin allele adopts a non-B conformation and contains a hot spot for DNA damage
Copyright policy )Premutation huntingtin allele adopts a non-B conformation and contains a hot spot for DNA damage
The expansion of a CAG trinucleotide repeat (TNR) sequence has been linked to several neurological disorders, for example, Huntington's disease (HD). In HD, healthy individuals have 5-35 CAG repeats. Those with 36-39 repeats have the premutation allele, which is known to be prone to expansion. In the disease state, greater than 40 repeats are present. Interestingly, the formation of non-B DNA conformations by the TNR sequence is proposed to contribute to the expansion. Here we provide the first structural and thermodynamic analysis of a premutation length TNR sequence. Using chemical probes of nucleobase accessibility, we found that similar to (CAG)(10), the premutation length sequence (CAG)(36) forms a stem-loop hairpin and contains a hot spot for DNA damage. Additionally, calorimetric analysis of a series of (CAG)(n) sequences, that includes repeat tracts in both the healthy and premutation ranges, reveal that thermodynamic stability increases linearly with the number of repeats. Based on these data, we propose that while non-B conformations can be formed by TNR tracts found in both the healthy and premutation allele, only sequences containing at least 36 repeats have sufficient thermodynamic stability to contribute to expansion.
- Brown University United States
Huntingtin Protein, Nuclear Proteins, Nerve Tissue Proteins, Calorimetry, Huntington Disease, Trinucleotide Repeats, Peroxynitrous Acid, Mutation, Humans, Nucleic Acid Conformation, Transition Temperature, DNA, B-Form, Alleles, DNA Damage
Huntingtin Protein, Nuclear Proteins, Nerve Tissue Proteins, Calorimetry, Huntington Disease, Trinucleotide Repeats, Peroxynitrous Acid, Mutation, Humans, Nucleic Acid Conformation, Transition Temperature, DNA, B-Form, Alleles, DNA Damage
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).2 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Average influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Average impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Average
Citations provided by BIP!Popularity provided by BIP!