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How cancer cells can become immortal – new research uncovers a mutated gene that helps melanoma beat the normal limits of repeated replication

How cancer cells can become immortal – new research uncovers a mutated gene that helps melanoma beat the normal limits of repeated replication

Melanom je posebno agresivan oblik raka kože.  <a href=Dlumen/iStock via Getty Images Plus” src=”https://s.yimg.com/ny/api/res/1.2/JKfGLecWopOacUWPbNi7hw–/YXBwaWQ9aGlnaGxhbmRlcjt3PTcwNTtoPTU1OA–/https://media.zenfs.com/en/the_conversation_us_articles_815/611d96d6cfd12cf9d5d2aa559cdc895d” data-src= “https://s.yimg.com/ny/api/res/1.2/JKfGLecWopOacUWPbNi7hw–/YXBwaWQ9aGlnaGxhbmRlcjt3PTcwNTtoPTU1OA–/https://media.zenfs.com/en/the_conversation_us_articles_815/611d96d6cfd12cf9d5d2aa559cdc895d”/>

The defining characteristic of cancer cells is their immortality. Normally, 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 “death” by continuing to multiply.

Telomeres they play an important role in determining how many times a cell can divide. These repetitive DNA sequences are found at the ends of chromosomes, the structures that contain genetic information. In normal cells, continuous 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 length of their telomeres by activating enzymes called telomerase which renews telomeres during each replication.

Telomere su zaštitne kapice na krajevima hromozoma.  <a href=FancyTapis/iStock via Getty Images Plus” data-src=”https://s.yimg.com/ny/api/res/1.2/nHmRWDCvYTkM91DVaralpQ–/YXBwaWQ9aGlnaGxhbmRlcjt3PTcwNTtoPTc2OA–/https://media.zenfs.com/en/the_conversation_us_articles_815/84515da2cac98fdf84272cdc9a8b02cc”/>

Telomerase is encoded by the so-called gene TERT, one of the most frequently mutated genes in cancer. TERT mutations cause cells to they make a little too much telomerase and are thought to help cancer cells keep their telomeres long even though they are replicating at high rates. Melanomaan aggressive form of skin cancer, largely depends on the growth of telomerase and three quarters of all melanomas get mutations in telomerase. These same TERT mutations also occur across the board other types of cancer.

Unexpectedly, the researchers found that TERT mutations can only partially explain telomere longevity in melanoma. Although TERT mutations did extend the lifespan of cells, they did not make them immortal. This meant that there must be something else that helps telomerase to allow cells to grow uncontrollably. But what that “second hit” could be, was not clear.

We are researchers studying the role of telomeres human health and disease like cancer in the Alder Laboratory at the University of Pittsburgh. By investigating the ways in which tumors maintain their telomeres, we and our colleagues found another piece of the puzzle: another telomere-related gene in melanoma.

Cellular immortality increases

Our team focused on melanoma because this type of cancer is associated with people with long telomeres. We examined DNA sequencing data from hundreds of melanomas, looking for mutations in genes associated with telomere length.

We identified a cluster of mutations in the so-called TPP1. This gene encodes one of the six proteins that form the so-called molecular complex shelter which coats and protects telomeres. Even more interesting is the fact that TPP1 is known activate telomerase. Identifying the link of the TPP1 gene to cancer telomeres was, in a way, obvious. After all, it was more than a decade ago that researchers have shown that TPP1 increases telomerase activity.

We tested whether excess TPP1 could render cells immortal. When we introduced only TPP1 proteins into the cells, there was no change in cell death or telomere length. But when we co-introduced the TERT and TPP1 proteins, we found that they acted synergistically to cause significant telomere lengthening.

To confirm our hypothesis, we next introduced TPP1 mutations into melanoma cells using CRISPR-Cas9 genome editing. We saw an increase in the amount of TPP1 protein that cells make and a subsequent increase in telomerase activity. Finally, we went back to the DNA sequencing data and found that 5% of all melanomas have a mutation in TERT and TPP1. Although this is still a significant proportion of melanomas, there are likely other factors that contribute to telomere maintenance in this cancer.

Our findings imply that TPP1 is likely one of the missing pieces of the puzzle that enhance the ability of telomerase to maintain telomeres and support tumor growth and immortality.

Make cancer fatal

Knowing that cancer uses these genes in its replication and growth means researchers could block them and potentially prevent telomere lengthening and make cancer cells lethal. The discovery not only gives scientists another potential avenue for cancer treatment, but also draws attention to an underappreciated class of mutations outside traditional gene boundaries that may play a role in cancer diagnosis.

This article was republished by Conversation, an independent, non-profit news site dedicated to sharing the ideas of academic experts. He wrote: Pattra Chun-On, University of Pittsburgh Health Sciences and Jonathan Alder, University of Pittsburgh Health Sciences. If you found it interesting, you could subscribe to our weekly newsletter.

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Jonathan Alder receives funding from the National Heart, Lung, and Blood Institute to support this work.

Pattra Chun-On does not work for, consult with, own stock or receive funding from any company or organization that would benefit from this article and has disclosed no relevant affiliations other than their academic appointment.



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