Abstract: During the progression of Telosens work, novel mechanisms of telomere maintenance were identified. Previous work of Maria Blasco and her team (partner CNIO) provide evidence for the implication of epigenetic mechanisms in the regulation of mammalian telomere length and function. Now, they have been successful in defining novel roles of SUV4-20 methyl transferases and the Retinoblastoma family of proteins (Rb, p107 and p130) in the interplay between heterochromatic features at telomeres and telomere length regulation.
In particular, loss of these proteins was found to increase the accessibility of heterochromatin facilitating the access of telomerase or other telomere-elongating activities to the chromosome end. Maria Blasco and her team further demonstrated a direct interaction between the Rb proteins and the H4K20 tri-methylating enzymes Suv4-20h1 and Suv4-20h2, suggesting a role of the Rb family in controlling H4-K20 tri-methylation by these novel histone methyltransferases. The observation that the Rb family is involved in maintaining overall chromatin structure and in particular that of constitutive heterochromatin including telomeric regions links telomere length, tumour suppression and the epigenetic definition of chromatin. More recently, a role for DNA methyltransferases has been shown by Blasco and colleagues in telomere length regulation and telomere recombination.
In particular, cells deficient in DNA methyltransferases showed a marked decreased in methylation of subtelomeric regions, which was coincidental with massive telomere elongation as well as with an increased telomeric recombination. The increased telomere recombination was also coincidental with increased presence of ALT-associated PML bodies (APB) in cells, which are a landmark for ALT mechanisms. These data suggest that DNA methylation acts repressing telomere recombination, therefore maintaining telomere integrity and telomere length.