Telomeres, protective caps at the of the end of the chromosome, are required to prevent DNA from degrading. In healthy cells, telomeres become shorter with each cycle of replication until they become so short that the cell can no longer divide. Disruptions in maintenance of the length of the telomeres can lead to severe disease. Short telomere syndromes lead to premature aging and death, but extra-long telomeres are associated with cancer.
For years, scientists have observed strikingly long telomeres in melanoma tumors, especially in comparison with other cancer types. The telomerase protein is responsible for elongating telomeres, protecting them from damage and preventing cell death. Telomerase is inactive in most cells, but many types of cancers use mutations in the telomerase gene, TERT, that activate this protein and allow cells to continue growing. Melanoma is particularly well-known for doing just this.
About 75% of melanoma tumors contain mutations in the TERT gene that stimulate protein production and increase telomerase activity. Yet, when scientists mutated TERT in melanocytes, they weren’t able to produce the same long telomeres seen in their patient’s tumors. It turned out that TERT promoter mutations were just half of the story.
“There’s some special link between melanoma and telomere maintenance,” said Jonathan Alder, Ph.D., assistant professor at the University of Pittsburgh School of Medicine. “For a melanocyte to transform into cancer, one of the biggest hurdles is to immortalize itself. Once it can do that, it’s well on its way to cancer.”
They found that the mutations in TPP1 were strikingly similar to those of TERT; they were located in the newly annotated promoter region of TPP1 and stimulated production of the protein. When they added mutated TERT and TPP1 back to cells, the two proteins synergized to create the distinctively long telomeres seen in melanoma tumors. TPP1 was the missing factor they had been searching for, and it was hiding in plain sight all along.
This discovery may change the way scientists understand the onset of melanoma, but it also has the potential to improve treatment. By identifying a telomere maintenance system that is unique to cancer, scientists have a new target for treatments.