PDF(Pubmed)
Abstract：
Cutaneous melanoma, a lethal skin cancer, arises from malignant transformation of melanocytes. Solar ultraviolet radiation (UVR) is a major environmental risk factor for melanoma since its interaction with the skin generates DNA damage, either directly or indirectly via oxidative stress. Pheomelanin pigments exacerbate oxidative stress in melanocytes by UVR-dependent and independent mechanisms. Thus, oxidative stress is considered to contribute to melanomagenesis, particularly in people with pheomelanic pigmentation. The melanocortin 1 receptor gene (MC1R) is a major melanoma susceptibility gene. Frequent MC1R variants (varMC1R) associated with fair skin and red or yellow hair color display hypomorphic signaling to the cAMP pathway and are associated with higher melanoma risk. This association is thought to be due to production of photosensitizing pheomelanins as well as deficient induction of DNA damage repair downstream of varMC1R. However, the data on modulation of oxidative DNA damage repair by MC1R remain scarce. We recently demonstrated that varMC1R accelerates clearance of reactive oxygen species (ROS)-induced DNA strand breaks in an AKT-dependent manner. Here we show that varMC1R also protects against ROS-dependent formation of 8-oxodG, the most frequent oxidative DNA lesion. Since the base excision repair (BER) pathway mediates clearance of these DNA lesions, we analyzed induction of BER enzymes in human melanoma cells of varMC1R genotype. Agonist-mediated activation of both wildtype (wtMC1R) and varMC1R significantly induced OGG and APE-1/Ref1, the rate-limiting BER enzymes responsible for repair of 8-oxodG. Moreover, we found that NADPH oxidase (NOX)-dependent generation of ROS was responsible for AKT activation and oxidative DNA damage repair downstream of varMC1R. These observations provide a better understanding of the functional properties of melanoma-associated MC1R alleles and may be useful for the rational development of strategies to correct defective varMC1R responses for efficient photoprotection and melanoma prevention in fair-skinned individuals.
摘要：
皮肤黑色素瘤，一种致命的皮肤癌,源于黑素细胞的恶性转化。太阳紫外线辐射（UVR）是黑色素瘤的主要环境危险因素，因为它与皮肤的相互作用会导致DNA损伤，直接或间接通过氧化应激。黑色素色素通过UVR依赖性和独立机制加剧黑素细胞的氧化应激。因此，氧化应激被认为是导致黑色素生成的原因，特别是在有软骨素色素沉着的人中。黑皮质素1受体基因(MC1R)是一个主要的黑色素瘤易感基因。与白皙皮肤和红色或黄色头发颜色相关的频繁MC1R变体(varMC1R)显示cAMP途径的低形态信号,并且与较高的黑色素瘤风险相关。这种关联被认为是由于产生了光敏化的软木素以及对varMC1R下游的DNA损伤修复的诱导不足。然而,关于MC1R对氧化性DNA损伤修复的调节的数据仍然很少。我们最近证明varMC1R以AKT依赖性方式加速活性氧（ROS）诱导的DNA链断裂的清除。在这里，我们表明varMC1R还可以防止8-oxodG的ROS依赖性形成，最常见的氧化性DNA损伤。由于碱基切除修复（BER）途径介导了这些DNA损伤的清除，我们分析了varMC1R基因型的人黑色素瘤细胞中BER酶的诱导。激动剂介导的野生型（wtMC1R）和varMC1R的激活均显着诱导OGG和APE-1/Ref1，这是负责修复8-oxodG的限速BER酶。此外，我们发现NADPH氧化酶（NOX）依赖性的ROS的产生负责AKT激活和varMC1R下游的氧化DNA损伤修复。这些观察结果提供了对黑素瘤相关MC1R等位基因的功能特性的更好理解，并且可能有助于合理制定策略，以纠正有缺陷的MC1R反应，以在皮肤白皙的个体中进行有效的光保护和黑素瘤预防。
