TERT promoter alterations could provide a solution for Peto's paradox in rodents.
Sci Rep
; 10(1): 20815, 2020 11 30.
Article
em En
| MEDLINE
| ID: mdl-33257697
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Roedores
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Regiões Promotoras Genéticas
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Telomerase
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Tamanho Corporal
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Fator de Transcrição de Proteínas de Ligação GA
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article