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Premutation huntingtin allele adopts a non-B conformation and contains a hot spot for DNA damage.

Abstract：

: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.

journal_name

Biochem Biophys Res Commun

journal_title

Biochemical and biophysical research communications

authors

Jarem DA,Delaney S

doi

10.1016/j.bbrc.2011.11.013

subject

Has Abstract

pub_date

2011-12-09 00:00:00

pages

146-52

issue

1-2

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(11)02012-2

journal_volume

416

pub_type

杂志文章

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