Science: How melanoma maintains telomere length and achieves immortality

Overcoming death and moving towards immortality is a crucial step
in the cell's march toward cancer.

Telomeres are protective cap structures at the ends of chromosomes, and as cells divide, telomeres become shorter and shorter
.
Telomerase maintains telomere length, allowing cells to continue dividing
.
In most cells, telomerase is inactive, but many cancers have mutations in the telomerase coding gene TERT, which activates telomerase, allowing cells to continue growing
.

Nearly 75% of melanoma carry a TERT mutation
.
However, inserting a TERT mutation into melanocytes does not produce the long telomeres
observed in melanoma patients.
As it turns out, mutations in the TERT promoter are only half
the story.

A study published in the journal Science showed that malignant melanocytes work together to accomplish this task through two steps, activating telomerase and TPP1 expression
.
TPP1 (tripeptidyl peptidase 1) is an telomere-binding protein that recruits telomerase onto telomeres
.

Mutations in TPP1 and telomerase synergistically lengthen the protective cap at the end of the chromosome, preventing the normal process of replicating aging
.
Replicative senescence causes cells to age with each replication cycle and eventually die
due to telomere shortening.
Identifying combinations of mutations in melanoma holds promise to change the way
clinicians understand and treat melanoma.

Co-corresponding author Jonathan Alder, Ph.
D.
, assistant professor of medicine at the University of Pittsburgh School of Medicine, said, "There are some special links
between melanoma and telomere maintenance.
One of the biggest obstacles in the process of melanocytes becoming cancerous is immortality
.
Once it can do that, people are at high risk of developing cancer
.
”

The promoter mutation of the TERT, although able to activate telomerase, is not sufficient to maintain telomere length
.
Dr.
Pattra Chun-on in Alder's lab was determined to find the missing link
that sustains long telomeres.
In earlier studies, Alder's team identified a region in the telomere-binding protein TPP1, which is often mutated
in melanoma.
Mutations in the TPP1 promoter occur in about 5% of cutaneous melanoma and occur simultaneously with mutations in the TERT promoter
.

Chun-on found that the mutation in TPP1 was similar
to that of the TERT.
Both sets of mutations are located in the promoter region
of their respective genes.
These mutations produce or modify the binding site of the transcription factor ETS, stimulating the expression
of gene products.

Adler thinks this is interesting because TPP1 is known to stimulate telomerase activity
.
"Biochemists discovered more than a decade ago that TPP1 could increase telomerase activity in test tubes, but we never knew this was actually happening clinically," he said
.

Chun-on mutated the genes for telomerase and TPP1 in cells and observed significant elongation
of telomeres in melanoma.
The alteration of the TPP1 promoter works synergistically with TERT activation to maintain long telomeres and immortalize melanoma cells, which increases our understanding of the telomere maintenance system in cancer and is expected to improve cancer treatment
.

Original search

TPP1 promoter mutations cooperate with TERT promoter mutations to lengthen telomeres in melanoma