Trinucleotide repeat DNA alters structure to minimize the thermodynamic impact of 8-oxo-7,8-dihydroguanine

Biochemistry. 2012 Jan 10;51(1):52-62. doi: 10.1021/bi201552s. Epub 2011 Dec 14.

Abstract

In the phenomenon of trinucleotide repeat (TNR) expansion, an important interplay exists between DNA damage repair of 8-oxo-7,8-dihydroguanine (8-oxoG) and noncanonical structure formation. We show that TNR DNA adapts its structure to accommodate 8-oxoG. Using chemical probe analysis, we find that CAG repeats composing the stem-loop arm of a three-way junction alter the population of structures in response to 8-oxoG by positioning the lesion at or near the loop. Furthermore, we find that oligonucleotides composed of odd-numbered repeat sequences, which form populations of two structures, will also alter their structure to place 8-oxoG in the loop. However, sequences with an even number of repeats do not display this behavior. Analysis by differential scanning calorimetry indicates that when the lesion is located within the loop, there are no significant changes to the thermodynamic parameters as compared to the DNA lacking 8-oxoG. This contrasts with the enthalpic destabilization observed when 8-oxoG is base-paired to C and indicates that positioning 8-oxoG in the loop avoids the thermodynamic penalty associated with 8-oxoG base-pairing. Since formation of stem-loop hairpins is proposed to facilitate TNR expansion, these results highlight the importance of defining the structural consequences of DNA damage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Base Sequence
  • Calorimetry, Differential Scanning / methods
  • DNA Damage / genetics*
  • DNA Repair / genetics*
  • DNA, Single-Stranded / chemistry
  • DNA, Single-Stranded / genetics
  • Guanine / analogs & derivatives*
  • Guanine / chemical synthesis
  • Humans
  • Huntington Disease / genetics
  • Molecular Sequence Data
  • Nucleic Acid Conformation*
  • Reactive Oxygen Species / chemistry
  • Reactive Oxygen Species / toxicity
  • Thermodynamics*
  • Trinucleotide Repeat Expansion / genetics*

Substances

  • DNA, Single-Stranded
  • Reactive Oxygen Species
  • 8-hydroxyguanine
  • Guanine