Energetic coupling between clustered lesions modulated by intervening triplet repeat bulge loops: Allosteric implications for DNA repair and triplet repeat expansion

Abstract

Clusters of closely spaced oxidative DNA lesions present challenges to the cellular repair machinery. When located in opposing strands, base excision repair (BER) of such lesions can lead to double strand DNA breaks (DSB). Activation of BER and DSB repair pathways has been implicated in inducing enhanced expansion of triplet repeat sequences. We show here that energy coupling between distal lesions (8oxodG and/or abasic sites) in opposing DNA strands can be modulated by a triplet repeat bulge loop located between the lesion sites. We find this modulation to be dependent on the identity of the lesions (8oxodG versus abasic site) and the positions of the lesions (upstream versus downstream) relative to the intervening bulge loop domain. We discuss how such bulge loop-mediated lesion cross talk might influence repair processes, while favoring DNA expansion, the genotype of triplet repeat diseases.

APE1 Incision Activity at Abasic Sites in Tandem Repeat Sequences

“…The observed position-dependent variation in AP site energetics for the above sequence-controlled 40 mer constructs suggests coupling between the lesion and the oligomer ends, with there being a more pronounced effect the closer the lesion is to the end. Consistently, we previously had shown energetic coupling between abasic sites and nearby bulge loop structures ( 22, 23 ).…”

“…In the present study, we determined the ability of APE1 to cleave at abasic sites in a collection of tandem DNA repeat landscapes involving telomeric and CAG/CTG sequences. Our investigations indicate an effect of the location of an AP site on the efficiency of APE1 incision and reveal an empirical correlation between the impact on duplex stability of the substrate AP lesion and the proximal domains on the modulation of repair protein activity, an observation foreshadowed by our previous studies ( 22, 23 ). Such data indicate that DNA damage will be repaired or processed with different proficiency, and thus, that certain genomic regions/domains will be more prone to damage accumulation and mutagenesis.…”

“…Previous work found that an abasic site in the duplex or loop domain of a CAG repeat “bulge loop” DNA substrate can differentially affect the stability of the loop structure, implying that the lesion, and its position within the repeat, may play a role in TNR expansion ( 22, 29 ), a phenomenon common to inherited neurological disorders such as Huntington disease. We have extended these prior studies by examining whether the various AP site-containing CAG substrates affect processing by the human APE1 protein.…”

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

“…38 In other work, the same authors proposed allosteric coupling between a 8-oxoG and/or a THF abasic site in the Ω-DNA. 39, 40 This finding again demonstrates the ability of these lesions to alter the microstates adopted by the Ω-DNA. Besides an abasic site, here we provide structural and thermodynamic data that supports the notion that the CAG repeats can also adapt their structure to accommodate the oxidatively damaged nucleobase 8-oxoG.…”

Biological role of 8-oxo-2'-deoxyguanosine

“…Согласно исследо-ваниям Уолкера и Плама, если 8-oxo-dG образуется с двух сторон от сигма-петли (возникающей в участ-ке с тандемными повторами), с очень высокой ве-роятностью OGG-1 организует там двунитевой разрыв, который может приводить к изменению нуклеотидной последовательности. Как правило, вставляются лишние повторяющиеся триплеты [5]. Показано также, что дефицитный по репарационным ферментам штамм Pseudomonas aeruginosa стано-вится устойчивым к антибиотику ципрофлоксацину [6], а окислительный стресс является фактором, способствующим возникновению ципрофлоксацин-устойчивых мутантов P. aeruginosa.…”