A defining characteristic of cancer cells is their immortality. Usually, normal cells are limited in the number of times they can divide before they stop growing. Cancer cells, however, can overcome this limitation to form tumors and bypass “mortality” by continuing to replicate.
Telomeres play an essential role in determining how many times a cell can divide. These repetitive sequences of DNA are located at the ends of chromosomes, structures that contain genetic information. In normal cells, continued rounds of replication shorten telomeres until they become so short that they eventually trigger the cell to stop replicating. In contrast, tumor cells can maintain the lengths of their telomeres by activating an enzyme called telomerase that rebuilds telomeres during each replication.
Telomeres are protective caps at the ends of chromosomes.
FancyTapis/iStock via Getty Images Plus
Telomerase is encoded by a gene called TERT, one of the most frequently mutated genes in cancer. TERT mutations cause cells to make a little too much telomerase and are thought to help cancer cells keep their telomeres long even though they replicate at high rates. Melanoma, an aggressive form of skin cancer, is highly dependent on telomerase to grow, and three-quarters of all melanomas acquire mutations in telomerase. These same TERT mutations also occur across other cancer types.
Unexpectedly, researchers found that TERT mutations could only partially explain the longevity of telomeres in melanoma. While TERT mutations did indeed extend the life span of cells, they did not make them immortal. That meant there must be something else that helps telomerase allow cells to grow uncontrollably. But what that “second hit” might be has been unclear.
We are researchers who study the role telomeres play in human health and diseases like cancer in the Alder Lab at the University of Pittsburgh. While investigating the ways that tumors maintain their telomeres, we and our colleagues found another piece to the puzzle: another telomere-associated gene in melanoma.
Cancer is a result of uncontrollable cell growth.
Cell immortality gets a boost
Our team focused on melanoma because this type of cancer is linked to people with long telomeres. We examined DNA sequencing data from hundreds of melanomas, looking for mutations in genes related to telomere length.
We identified a cluster of mutations in a gene called TPP1. This gene codes for one of the six proteins that form a molecular complex called shelterin that coats and protects telomeres. Even more interesting is the fact that TPP1 is known to activate telomerase. Identifying the TPP1 gene’s connection to cancer telomeres was, in a way, obvious. After all, it was more than a decade ago that researchers showed that TPP1 would increase telomerase activity.
We tested whether having an excess of TPP1…
