TERT Gene

Introduction

Telomeres are DNA structures at the end of chromosomes meant to prevent chromosomes from unintentionally degrading or sticking together. Each time mitosis occurs, they shorten, until their length prevents further cell division and triggers cell death. The Telomerase Reverse Transcriptase (TERT) is a tumor suppressor gene located at 5p15.33.

Structure of human papillomavirus. (source)

The telomerase enzyme adds TTAGGG nucleotide repeats onto the telomeres each time the cell divides to compensate for the DNA lost during division. The shelterin complex, made up of six proteins (TRF1, TRF2, POT1, RAP1, TIN2, and TPP1), is responsible for both binding and protecting chromosome ends. Also involved in telomerase function, is RNA gene TERC, the Telomerase RNA component, which provides a blueprint for the development of telomeres.

Promoter Mutations

When mutations in the TERT gene occur, this can lead to an over-expression of telomerase. The telomerase enzyme and its ability to lengthen the telomere by adding small DNA segments allow cells to evade apoptosis. These mutations are evident in over fifty different types of cancer including those in the central nervous system, bladder, and skin. However, one of the cancers most affected by TERT mutations is Glioblastoma. Glioblastoma (GBM) is a rare brain or spinal cord cancer with a 6% five-year survival rate. Anyone can develop GBM, but the most common demographic are men in their mid-60s.

Normal and infected epithelium. Human papillomavirus penetrates the mucosal epithelium via microinjuries. (source)

It can be treated with a combination of surgery, radiation, and chemotherapy, but it is ultimately incurable. TERT promoter mutations have been found in around 80% of GBM cases, the two most frequent types being C228T and C250T. Both are C→T point mutations located at −124 and −146 from the transcription start site and have the ability to double expression. While TERTp mutations can be germline, they are usually somatic.

Further Study

As of right now, Glioblastoma is incurable, however, there is a treatment being developed to cure it. The treatment is a therapy meant to target TERT in GBM cases by involving eribulin chemotherapy, which is classified as a microtubule inhibitor. It had significant anti-tumor effects in testing, and it is in the process of clinical trials. Studies have also been conducted on the prospect of inducing telomerase inhibition. One study conducted regarding that subject on breast cancer had very promising results. They also noted how drugs meant to induce apoptosis could be made to be specific to cancer cells and not disturb regular cells, with the added benefit of not having serious side effects. Furthermore, as enabling replicative immortality is a consistent hallmark of cancer, this could be applicable to a wide variety of tumors. The possibility of using telomerase inhibitors as adjuvant supporting therapy, after surgery or another therapy is also being explored.

Treatment strategies for TERT promoter mutant tumors. Various treatment strategies taking advantage of the presence of TERT promoter mutations have been proposed, including targeting the GABPβ1L. (source)

Despite this, no therapies directed at telomerase have been successful yet, although some are currently in the clinical trial process. Some studies attribute this to the possibility that inhibition might not work fast enough after rapid enough proliferation. To conclude, several ways of curing cancer involving the TERT gene are being investigated. While none have been successful so far, the results have been encouraging and such a therapy would be very valuable due to the number of cancers that have TERT mutations.

_ By: By: Sahana Shetty (Horizon High School)_ (External student, guest post on the request of Mentors)

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661921/

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678952/

3. https://www.frontiersin.org/articles/10.3389/fimmu.2020.589929/full

4. https://link.springer.com/article/10.1007/s40291-018-0336-x

5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226422/

6. https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Glioblastoma-Multiforme

7. https://www.mayoclinic.org/diseases-conditions/glioblastoma/cdc-20350148

8. https://academic.oup.com/noa/article/2/1/vdaa025/5763093

9. https://www.sciencedirect.com/science/article/pii/S030438352030358X#undfig1

10. https://www.pnas.org/doi/full/10.1073/pnas.1303607110

11. https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-016-0324-x

12. https://medlineplus.gov/genetics/gene/tert

13. https://modbase.compbio.ucsf.edu/modbase-cgi/model_details.cgi

14. https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=TERT

15. https://www.cbioportal.org/results/oncoprint

16. https://www.ncbi.nlm.nih.gov/gene/7015

17. https://www.uniprot.org/uniprotkb/O14746/entry

18. https://www.nature.com/articles/ncomms3185​​

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of Elio Academy.