UV light-induced dual promoter mutations dismantle the telomeric guardrails in melanoma
Author: Samantha L Sanford1, Patricia L Opresko2
Affiliation:
1 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.
2 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. Electronic address: plo4@pitt.edu.
Conference/Journal: DNA Repair (Amst)
Date published: 2022 Dec 30
Other:
Volume ID: 122 , Pages: 103446 , Special Notes: doi: 10.1016/j.dnarep.2022.103446. , Word Count: 152
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.
Keywords: Melanoma; Promoter mutations; TPP1; Telomerase; Telomere biology; UV mutagenesis.
PMID: 36603239 DOI: 10.1016/j.dnarep.2022.103446
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