The role of chromatin structure in telomere capping
The establishment of a specific nucleoprotein structure, the telomere, is required to ensure the protection of chromosome ends from being recognized as DNA damage sites. In humans, telomeres consist of thousands of TTAGGG repeats bound by a six-protein complex named shelterin. The complete replication of telomeric repeats is assured by the enzyme telomerase, which is active only in germinal and stem cells. In somatic cells, telomeres shorten with each replication round till they reach a critical length leading to a cell cycle arrest known as replicative senescence. Mutations in the growth arrest pathway could allow cells to bypass senescence and continue dividing. Most telomeres uncap, resulting in a crisis stage characterized by chromosome end-fusions and massive apoptosis. To acquire unconstrained proliferative capacity, cancer cells must escape senescence and/or crisis by reactivating telomerase or by alternative mechanisms of telomere maintenance.
Telomeric chromatin has peculiar features: tight nucleosomal structure, enrichment in the histone variant H3.3 and specific heterochromatic histone marks. Mutations in genes responsible for the telomeric epigenetic pattern (SIRT6) or for H3.3 deposition at telomeres (ATRX, DAXX) are deleterious for the stability of human telomeres. Importantly, H3.3/ATRX/DAXX mutations are often found in ALT tumors, suggesting that they play a key role in ALT development.
Despite the essential role telomeres play in cancer development and in aging, our knowledge of the chromatin structure of protected and deprotected telomeres is still insufficient.
In this research project we will address two main issues:
1. The structural and epigenetic changes of human telomeres switching from a protected to a deprotected state.
2. The role played by nucleosomes in telomere capping and how they affect shelterin binding.