Available online 30 December 2022, 103446

Author links open overlay panelAbstract

Understanding how benign nevi can progress to invasive and metastatic melanoma 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.

Section snippetsAcknowledgments

Work in the Opresko lab is supported by NIH grants R35ES030396 and R01CA207342.

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