The case for 8,5'-cyclopurine-2'-deoxynucleosides as endogenous DNA lesions that cause neurodegeneration in xeroderma pigmentosum

Abstract

Patients with the genetic disease xeroderma pigmentosum (XP) lack the capacity to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from ultraviolet (UV) radiation. A subset of XP patients develops a profound neurodegenerative condition known as XP neurological disease. Robbins and colleagues [Andrews A, Barrett S, Robbins J (1978) Xeroderma pigmentosum neurological abnormalities correlate with the colony forming ability after ultraviolet irradiation. Proc Natl Acad Sci U S A 75:1984-1988] hypothesized that since UV light cannot reach into the human brain, XP neurological disease results from some form of endogenous DNA damage that is normally repaired by the NER pathway. In the absence of NER, the damage accumulates, causing neuronal death by blocking transcription. In this manuscript, I consider the evidence that a particular class of oxidative DNA lesions, the 8,5'-cyclopurine-2'-deoxynucleosides, fulfills many of the criteria expected of neurodegenerative DNA lesions in XP. Specifically, these lesions are chemically stable, endogenous DNA lesions that are repaired by the NER pathway but not by any other known process, and strongly block transcription by RNA polymerase II in cells from XP patients. A similar set of criteria might be used to evaluate other candidate DNA lesions responsible for neurological diseases resulting from defects in other DNA repair mechanisms as well.

Figure 1

Structures of the cyclopurine-deoxynucleoside lesions.

Figure 2

Mechanisms of formation of 8,5’-cyclo-dA versus 8-OH-dA, illustrating the ability of O₂ to inhibit cyclopurine-deoxynucleoside formation.

Figure 3

Potential sources of elevated oxidatively-induced DNA damage in catecholamine neurons that could increase result in increased cyclopurine-deoxynucleoside formation. Abbreviations: TH; tyrosine hydroxylase, DDC; dopa decarboxylase; MAO; monoamine oxidase. Note that both H₂O₂ and Fe could react to form the hydroxyl radical outside the nucleus, but such radicals would never reach the genomic DNA and are therefore not relevant to the mechanisms of XP neurological disease.