Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, USA; UPMC Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, USA; UPMC Hillman Cancer Center, University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA 15213, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, USA.
DNA Repair (Amst). 2023 Feb;122:103446. doi: 10.1016/j.dnarep.2022.103446. Epub 2022 Dec 30.
Understanding how benign nevi can progress to invasive and metastatic Department of Environmental and Occupational Health, University of Pittsburgh School of Public Health, USAelanoma is critical for developing interventions and therapeutics for this most deadly form of skin cancer. UV-induced mutations in the telomerase TERT gene promoter occur in the majority of melanomas but fail to prevent telomere shortening despite telomerase upregulation. This suggests additional "hits" are required to enable telomere maintenance. A new study in Science identified somatic variants in the promoter of the gene that encodes telomere shelterin protein TPP1 in human melanomas. These variants show mutational signatures of UV-induced DNA damage and upregulate TPP1 expression, which synergizes with telomerase to lengthen telomeres. This study provides evidence that TPP1 promoter variants are a critical second hit to prevent telomere shortening and promote immortalization of melanoma cells.
了解良性痣如何进展为侵袭性和转移性黑素瘤对于开发针对这种最致命形式皮肤癌的干预措施和疗法至关重要。在大多数黑素瘤中，端粒酶 TERT 基因启动子的紫外线诱导突变发生，但尽管端粒酶上调，仍未能防止端粒缩短。这表明需要额外的“打击”来维持端粒。一项发表在《科学》杂志上的新研究在人类黑素瘤中鉴定出编码端粒保护蛋白 TPP1 的基因启动子中的种系变异。这些变体显示出紫外线诱导的 DNA 损伤的突变特征，并上调 TPP1 的表达，这与端粒酶协同作用以延长端粒。这项研究提供了证据，表明 TPP1 启动子变体是防止端粒缩短和促进黑素瘤细胞永生化的关键第二次打击。
