New results from Titia de Lange’s lab (at the Rockefeller University) have provided the first piece of evidence that telomere shortening helps prevent cancer in humans, likely because of its power to restrict cell division.
Telomere shortening is a presumed tumour suppressor pathway. This model predicts that excessively long somatic telomeres predispose to cancer. In vitro observations have shown that telomere shortening leads to a proliferative barrier (the Hayflick limit). This can be overcome via telomerase activation through hTERT expression. Telomerase is a hallmark of human cancer and is required to create tumourigenic derivatives from normal human cells. Several hTERT promoter mutations have found in familial melanoma and other tumour types. This has further solidified the view that telomere attrition is a barrier to tumourigenesis.
For the telomere tumor suppression pathway to limit cancer incidence, telomeres need to shorten at the correct rate. In telomerase-positive tissue culture cells, telomere length homeostasis is mediated by shelterin. TIN2 is a central component of sheltrin. TIN2 interacts with both double-stranded telomeric DNA-binding proteins – TRF1 and TRD2. It also binds TPP1 which forms a heterodimer with the single-stranded telomeric DNA-binding protein POT1. TIN2 has been implicated as a negative regulatory of telomere length.
In this study, published in eLife, researchers described heterozygous loss-of-function mutations in TINF2 in cancer-prone families. Specifically, two unique TINF2 mutations that truncate TIN2. They found that these mutations did not compromise telomere protection but actually created excessively long telomeres in vitro and in vivo. They also showed that the truncated TN2 proteins did not localise to telomeres. Additionally, heterozygous knock-in of the mutations or deletion of one copy of TINF2 resulted in excessive telomere elongation in clonal lines. This indicates that TINF2 is haploinsufficient for telomere length control.
This data establishes that the TINF2 truncations predispose to a tumour syndrome. Specifically, TINF2 acts a haploinsufficient tumour suppressor that limits telomere length to ensure a timely Hayflick limit. The team conclude that the affected individuals are cancer-prone because their overly long telomeres impede the telomere tumour suppressor pathway.
De Lange, Leon Hess Professor at Rockefeller, stated:
“The data shows that if you’re born with long telomeres, you are at greater risk of getting cancer.
We are seeing how the loss of the telomere tumour suppressor pathway in these families leads to breast cancer, colorectal cancer, melanoma and thyroid cancers. These cancers would normally have been blocked by telomere shortening. The broad spectrum of cancers in these families shows the power of the telomere tumour suppressor pathway.”
Image credit: By Rost-9D – canva.com