TERT promoter alterations could provide a solution for Peto\u2019s paradox in rodents

Balázs Vedelek,Asha Kiran Maddali,Viktor Vedelek,Imre M Boros,Nurgul Davenova

doi:10.1038/s41598-020-77648-0

Balázs Vedelek, Asha Kiran Maddali + Show 3 more

Open Access

https://doi.org/10.1038/s41598-020-77648-0

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Abstract

Cancer is a genetic disease caused by changes in gene expression resulting from somatic mutations and epigenetic changes. Although the probability of mutations is proportional with cell number and replication cycles, large bodied species do not develop cancer more frequently than smaller ones. This notion is known as Peto’s paradox, and assumes stronger tumor suppression in larger animals. One of the possible tumor suppressor mechanisms involved could be replicative senescence caused by telomere shortening in the absence of telomerase activity. We analysed telomerase promoter activity and transcription factor binding in mammals to identify the key element of telomerase gene inactivation. We found that the GABPA transcription factor plays a key role in TERT regulation in somatic cells of small rodents, but its binding site is absent in larger beavers. Protein binding and reporter gene assays verify different use of this site in different species. The presence or absence of the GABPA TF site in TERT promoters of rodents correlates with TERT promoter activity; thus it could determine whether replicative senescence plays a tumor suppressor role in these species, which could be in direct relation with body mass. The GABPA TF binding sites that contribute to TERT activity in somatic cells of rodents are analogous to those mutated in human tumors, which activate telomerase by a non-ALT mechanism.

Highlights

Cancer is a genetic disease caused by changes in gene expression resulting from somatic mutations and epigenetic changes
The reason for the debate concerning the tumor suppressor role of replicative senescence is its similarity to induced senescence, which occurs from causes other than telomere shortening in cellular homeostasis during ageing of cells
In 14 of these species telomerase is active, while in the rest telomerase is inactive in somatic cells

Summary

Introduction

Cancer is a genetic disease caused by changes in gene expression resulting from somatic mutations and epigenetic changes. In somatic cells of mice and other small rodents the TERT promoter is a ctive[21] In these rodents, the tumor suppressor effect of telomere shortening may never be essential or take place because their lifespan is short and fewer number of cell divisions are necessary to reach the final body mass compared to large m ammals[6,7]. Exceptions are beavers and capybaras, in which the telomerase activity is lower than in other rodents These species have larger body masses, at which replicative senescence could be beneficial. Revealing the importance of a cis-acting element in TERT gene inactivation highlights an evolutionary mechanism that allowed longevity and increased fitness of large bodied animals, and our vulnerability to acquired mutations providing an ideal cellular environment for the development of cancer

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