High levels of oxidatively generated DNA damage 8,5′-cyclo-2′-deoxyadenosine accumulate in the brain tissues of xeroderma pigmentosum group A gene-knockout mice

Add time:09/09/2019    Source:sciencedirect.com

Xeroderma pigmentosum (XP) is a genetic disorder associated with defects in nucleotide excision repair, a pathway that eliminates a wide variety of helix-distorting DNA lesions, including ultraviolet-induced pyrimidine dimers. In addition to skin diseases in sun-exposed areas, approximately 25% of XP patients develop progressive neurological disease, which has been hypothesized to be associated with the accumulation of an oxidatively generated type of DNA damage called purine 8,5′-cyclo-2′-deoxynucleoside (cyclopurine). However, that hypothesis has not been verified. In this study, we tested that hypothesis by using the XP group A gene-knockout (Xpa−/−) mouse model. To quantify cyclopurine lesions in this model, we previously established an enzyme-linked immunosorbent assay (ELISA) using a monoclonal antibody (CdA-1) that specifically recognizes 8,5′-cyclo-2′-deoxyadenosine (cyclo-dA). By optimizing conditions, we increased the ELISA sensitivity to a detection limit of ˜one cyclo-dA lesion/106 nucleosides. The improved ELISA revealed that cyclo-dA lesions accumulate with age in the brain tissues of Xpa−/− and of wild-type (wt) mice, but there were significantly more cyclo-dA lesions in Xpa−/− mice than in wt mice at 6, 24 and 29 months of age. These findings are consistent with the long-standing hypothesis that the age-dependent accumulation of endogenous cyclopurine lesions in the brain may be critical for XP neurological abnormalities.

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