Mice with bad ends: mouse models for the study of telomeres and telomerase in cancer and aging

Abstract

Telomeres are capping structures at the ends of eukaryotic chromosomes, which consist of repetitive DNA bound to an array of specialized proteins. Telomeres are part of the constitutive heterochromatin and are subjected to epigenetic modifications. The function of telomeres is to prevent chromosome ends from being detected as damaged DNA. Both the length of telomere repeats and the integrity of the telomere-binding proteins are important for telomere protection. Telomere length is regulated by telomerase, by the telomere-binding proteins, as well as by activities that modify the state of the chromatin. Various mouse models with altered levels of telomerase activity, or mutant for different telomere-binding proteins, have been recently generated. Here, I will discuss how these different mouse models have contributed to our understanding on the role of telomeres and telomerase in cancer and aging.

Figure 1

Telomere-binding proteins. Scheme showing the telomere in a T-loop conformation, as well as with different protein complexes found at mammalian telomeres. The TRF1 complex has been shown to influence telomere length, while the TRF2 complex has been shown to influence both telomere length and telomere capping.

Figure 2

Assembly of telomeric heterochromatin. Mammalian telomeres contain features of the constitutive heterochromatin such as enrichment for H3-K9 di- and trimethylation, as well as binding of the HP1 family of proteins, similar to that previously described for pericentric hetochromatin. The Suv39h1 and Suv39h2 HMTases are required for the di-and trimethylation of H3-K9 at telomeres, which in turn recruits the HP1 proteins. Telomeric chromatin in SUV39DN cells also shows decreased binding of the HP1 proteins. These epigenetic modifications contribute to a ‘closed' chromatin state, which may regulate the access of telomerase to the telomeres.

Figure 3

Role of telomerase in tumorigenesis. Telomerase is re-activated in more than 90% of all types of human tumors. Telomerase re-activation in tumors confers a proliferative advantage through two mechanisms: (i) rescue of critically short telomeres and prevention of cell death or cell arrest, (ii) telomere-length independent effects on survival and proliferation.

Figure 1

María A Blasco