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.
