The 8,5'-cyclopurine-2'-deoxynucleosides: candidate neurodegenerative DNA lesions in xeroderma pigmentosum, and unique probes of transcription and nucleotide excision repair

Abstract

It is a commonly held view that oxidatively induced DNA lesions are repaired by the base excision repair (BER) pathway, whereas DNA lesions induced by UV light and other "bulky" chemical adducts are repaired by the nucleotide excision repair (NER) pathway. While this distinction is generally accurate, the 8,5'-cyclopurine deoxynucleosides represent an important exception, in that they are formed in DNA by the hydroxyl radical, but are specifically repaired by NER, not by BER. They are also strong blocks to nucleases and polymerases, including RNA polymerase II in human cells. In this review, I will discuss the evidence that these lesions are in part responsible for the neurodegeneration that occurs in some XP patients, and what additional evidence would be necessary to prove such a role. I will also consider other DNA lesions that might be involved in XP neurologic disease. Finally, I will also discuss how our recent studies of these lesions have generated novel insights into the process of transcriptional mutagenesis in human cells, as well as the value of studying these lesions not only for a better understanding of NER but also for other aspects of human health and disease.

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Chemical structures of the R and S forms of the cyPudNs.

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The mechanism of cyPudN formation, and the role of molecular oxygen in preventing lesion formation.

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Energy-minimized models of dA (left panels) and 8, 5’-(S) cyclo-dA (right panels) viewed from different perspectives. Modeling was carried out using YASARA-WHATIF (www.Yasara.com)[23]. In the top panels, the distance between the 5’ and 8 carbons is indicated. For comparison, the measured distance between the 5’ and 8 carbons in a crystal structure of cyclo-A is 1.513 Å [26].

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RNA transcripts resulting from bypass of cyclo-dA in human cells [56]. The double-stranded DNA template that was transfected into cells is shown at the bottom. The location of the cyclo-dA lesion is indicated by the red italic A.