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Journal of Undergraduate Research

Keywords

TRF1 mutations, mechanism for telomere length maintenance, cancer

College

Life Sciences

Department

Physiology and Developmental Biology

Abstract

Telomeres are repetitive DNA sequences found on the ends of chromosomes that serve to protect the genes contained within each chromosome. As a cell replicates, its telomeres shorten, eventually triggering cellular senescence or death. This serves as a tumor suppressive mechanism by limiting the proliferation of cells. All cancers must overcome this growth limitation by acquiring mutations that permit telomere elongation. Most cancers achieve this by acquiring activating-mutations in an enzyme known as telomerase. Some cancers do not express telomerase, and maintain their telomeres by other means including a mechanism called “alternative lengthening of telomeres” (ALT). However, there exists a subset of cancers that possess neither of these telomere-maintenance mechanisms.

Telomeres functions by binding a set of proteins collectively known as shelterin, which regulate telomere length maintenance and serve to protect the chromosomal termini from being recognized by the cell as broken DNA. We recently identified several single-codon variations within the shelterin component TRF1 in a sample of lung cancer genomes that lacked either telomerase or ALT activation, suggesting that the telomeres of these cancer samples were maintained by a potentially novel mechanism. These variations were located in the DNA-binding domain of TRF1, called the Myb-Domain, which was previously shown to be necessary for TRF1’s binding to telomeric DNA. The wild-type sequence of the affected codons is extremely conserved among many species, suggesting that these residues may play a functional role in the protein. The discovery of a new mechanism of telomere maintenance would elucidate potential therapeutic targets in associated cancers and enhance our understanding of the process of malignant transformation.

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