Trinucleotide Repeat DNA Alters Structure To Minimize the Thermodynamic Impact of 8-Oxo-7,8-dihydroguanine

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 non-canonical 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.

APE1 Incision Activity at Abasic Sites in Tandem Repeat Sequences

“…Although CAG6Fn:CTG2 can form three distinct loop isomers “on paper”, it is likely that only two are resolvable on a gel, as two of the loop isomers (i.e., the one with a long upstream and short downstream arm, and the one with a long downstream and short upstream arm) are expected to have very similar hydrodynamic properties. The fact that we observed only one major species for CAG6F3:CTG2 suggests that for this oligomer arrangement the different loop isomers are not resolvable, or more likely, that only one of the isomers is populated to a significant extent ( 32 ).…”

Oxidative DNA Damage Modulates Trinucleotide Repeat Instability Via DNA Base Excision Repair

“…Thus, our results demonstrate that the 8-oxoG and THF residue (abasic site) were located in the loop region rather than in the stem of the hairpin substrates. This is consistent with a finding showing that a DNA base lesion such as an 8-oxoG is preferentially located in the loop region of a hairpin (203). We then determined the activities of OGG1 and APE1 on these substrates and discovered that 70% of 8-oxoG in the loop region of a small (CAG) 7 …”

“…Guanines located at the loop region of a TNR hairpin are hypersensitive to oxidative DNA damaging agents such as peroxynitrite (202). Moreover the oxidized base lesion 8-oxoG located in the stem region of a CAG repeat hairpin is preferentially relocated to the loop region via a dynamic intrastrand rearrangement of the repeats (203). However, it was shown that a base lesion in a hairpin loop that was detached from a CAG repeat tract was refractory to cleavage by 8-oxoG DNA glycosylase (OGG1) (204).…”

Investigation of Base Pairs Containing 7,8-Dihydro-8-oxoguanine by Quantum Chemistry

“…DNA 的损 伤导致了细胞的衰老、疾病恶化及癌症的发生 [2,3] . 在 DNA 的四种核酸碱基中鸟嘌呤(G)具有最小的电离势 [7] , C8 位 最 容 易 被 氧 化 , 生 成 7,8-二 氢 -8-氧 -鸟 嘌 呤 (8-oxo-G) [8,9] , 它可以导致 G→T 的转换 [2～6] . 在 DNA 复 制过程中, 8-oxo-G 会被聚合酶误识别为其他的碱基与 正常碱基发生错配, 这些都将导致一个错误基因编码的 信息 [10] .…”