端粒酶活化是黑色素瘤发生的关键步骤，常常是由于紫外线辐射（UVR）诱导造成的端粒酶基因（TERT）启动子发生突变，进而通过BRAFV600E突变激活的Raf-MAP激酶途径促使TERT转录。由于小鼠的端粒过长，在小鼠模型中，这个过程不会发生在黑色素瘤发生的过程中。为了研究端粒功能障碍对黑色素瘤发生发展的影响，我们在Tert-/-小鼠的第1代和第4代（G1和G4）中诱导了BrafV600E。我们的研究结果显示，无论紫外线暴露与否，与第1代和野生型C57BL/6J（G0）小鼠相比，G4小鼠（具有较短的端粒）的黑色素瘤发展被延迟。此外，许多G4肿瘤显示了过量DNA损伤的积累，通过增加γH2A.X染色来证明。紫外线暴露小鼠的肿瘤表现出p53蛋白表达增加。从G4小鼠中分离的培养肿瘤细胞显示了大量染色体融合和重排，表明这些细胞存在端粒功能障碍。此外，从紫外线B（UVB）暴露小鼠中获得的肿瘤细胞表现出突变p53蛋白的持续高表达，这表明p53是UVB诱导的突变的靶点。综上所述，我们的研究结果表明端粒功能障碍阻碍了黑色素瘤的发生发展。针对端粒危机介导的基因组不稳定性可能在黑色素瘤的预防和治疗中具有潜力。© 2023 UICC.

Telomerase activation is a crucial step in melanomagenesis, often occurring because of ultraviolet radiation (UVR)-induced mutations at the telomerase gene (TERT) promoter and rendering TERT transcription in response to the activated Raf-MAP kinase pathway by BRAFV600E mutation. Due to the excessively long telomeres in mice, this process does not occur during melanomagenesis in mouse models. To investigate the impact of telomere dysfunction on melanomagenesis, BrafV600E was induced in generations 1 and 4 (G1 and G4) of Tert-/- mice. Our findings revealed that, regardless of UVR exposure, melanoma development was delayed in G4 mice, which had shorter telomeres compared to G1 and wild-type C57BL/6J (G0) mice. Moreover, many G4 tumors displayed an accumulation of excessive DNA damage, as evidenced by increased γH2A.X staining. Tumors from UVR-exposed mice exhibited elevated p53 protein expression. Cultured tumor cells isolated from G4 mice displayed abundant chromosomal fusions and rearrangements, indicative of telomere dysfunction in these cells. Additionally, tumor cells derived from UVB-exposed mice exhibited constitutively elevated expression of mutant p53 proteins, suggesting that p53 was a target of UVB-induced mutagenesis. Taken together, our findings suggest that telomere dysfunction hampers melanomagenesis, and targeting telomere crisis-mediated genomic instability may hold promise for the prevention and treatment of melanoma.© 2023 UICC.