Xeroderma Pigmentosum C (XPC) is a multi-functional protein that is involved not only in the repair of bulky lesions, post-irradiation, via nucleotide excision repair (NER) per se but also in oxidative DNA damage mending. Since base excision repair (BER) is the primary regulator of oxidative DNA damage, we characterized, post-Ultraviolet B-rays (UVB)-irradiation, the detailed effect of three different XPC mutations in primary fibroblasts derived from XP-C patients on mRNA, protein expression and activity of different BER factors. We found that XP-C fibroblasts are characterized by downregulated expression of different BER factors including OGG1, MYH, APE1, LIG3, XRCC1, and Polβ. Such a downregulation was also observed at OGG1, MYH, and APE1 protein levels. This was accompanied with an increase in DNA oxidative lesions, as evidenced by 8-oxoguanine levels, immediately post-UVB-irradiation. Unlike in normal control cells, these oxidative lesions persisted over time in XP-C cells having lower excision repair capacities. Taken together, our results indicated that an impaired BER pathway in XP-C fibroblasts leads to longer persistence and delayed repair of oxidative DNA damage. This might explain the diverse clinical phenotypes in XP-C patients suffering from cancer in both photo-protected and photo-exposed areas. Therapeutic strategies based on reinforcement of BER pathway might therefore represent an innovative path for limiting the drawbacks of NER-based diseases, as in XP-C case.

Xerderma Pigmentosum C（XPC）是一种多功能蛋白，不仅通过放射切除修复（NER）参与放射后大体积病变的修复。 本身而且在氧化性DNA损伤修复中。由于碱基切除修复（BER）是氧化DNA损伤的主要调节剂，因此我们对紫外线B射线（UVB）辐射进行了表征，得出了XP-C患者衍生的原代成纤维细胞中三种不同XPC突变对mRNA的详细影响，蛋白质表达和不同BER因子的活性。我们发现XP-C成纤维细胞的特征在于不同BER因子的表达下调，包括OGG1， MYH， APE1， LIG3， XRCC1和 波尔β。在OGG1，MYH和APE1蛋白水平上也观察到这种下调。伴随着DNA氧化损伤的增加，如UVB照射后立即由8-氧鸟嘌呤水平所证明的。与正常对照细胞不同，这些氧化损伤在具有较低切除修复能力的XP-C细胞中随时间持续存在。两者合计，我们的结果表明XP-C成纤维细胞中的BER通路受损导致更长的持久性和氧化DNA损伤的修复延迟。这可能解释了受光保护和受光照射的地区患有癌症的XP-C患者的不同临床表型。因此，与XP-C案例一样，基于BER途径增强的治疗策略可能代表了一种限制NER疾病弊端的创新途径。