Kyung Ah Cheong, Ai-Young Lee
DOI: 10.2340/00015555-3473

DNA damage and oxidative stress play a critical role in photoageing. Seborrhoeic keratosis (SK) affects sunlight-exposed sites in aged individuals. This study examined the mechanism of photoageing in SK. The guanine deaminase gene, which is involved in purine metabolism, was upregulated with uric acid levels and p21 in SK. Guanine deaminase was detectable in keratinocytes. Repeated exposure to ultraviolet (UV) increased levels of guanine deaminase, together with DNA damage, such as γ-H2AX and cyclobutane pyrimidine dimer formation, generation of reactive oxygen species, and keratinocyte senescence, which were reversed by guanine deaminase knockdown. However, guanine deaminase overexpression and H2O2 formed γ-H2AX, but not cyclobutane pyrimidine dimer. Loss-of-function guanine deaminase mutants reduced the metabolic end-product uric acid, which was increased by exposure to exogenous xanthine. Repeated exposure to UV increased levels of uric acid. Exogenous uric acid increased cellular senescence, reactive oxygen species, and γ-H2AX, similar to guanine deaminase. Overall, guanine deaminase upregulation increased UV-induced keratinocyte senescence in SK, via uric acid mediated by reactive oxygen species followed by DNA damage.

Seborrhoeic keratosis develops mainly on sun-exposed areas of elderly individuals, suggesting that photoageing has a role in this condition. Based on evidence of purine degradation in skin following chronic exposure to sunlight, guanine deaminase was selected as a candidate gene related to purine metabolism. Although the expression of guanine deaminase in human keratinocytes has yet to be elucidated, this study demonstrated keratinocytes as the main source of guanine deaminase in skin. The role of guanine deaminase in ultraviolet (UV)-induced keratinocyte senescence was examined in seborrhoeic keratosis and primary cultured adult human keratinocytes. The results suggest that guanine deaminase upregulation in seborrhoeic keratosis mediates UV-induced keratinocyte senescence via the production of uric acid as an end-product, generating reactive oxygen species followed by DNA damage.

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