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.
DNA Repair (Amst)
; 80: 52-58, 2019 08.
Article
em En
| MEDLINE
| ID: mdl-31279170
ABSTRACT
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 Ëone 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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Base de dados:
MEDLINE
Assunto principal:
Xeroderma Pigmentoso
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Dano ao DNA
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Encéfalo
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Desoxiadenosinas
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Proteína de Xeroderma Pigmentoso Grupo A
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article