The Telosome: Deciphering the architecture of the shelterin complex and its network

Telomeres of eukaryotic chromosomes are protected by the shelterin complex. The human shelterin is a six-subunit protein assembly (TRF1, TRF2, TPP1, POT1, TIN2, Rap1).

This complex associates with telomeric DNA and prevents the mistaken detection of the telomeres as double strand breaks by the DNA Damage Response (DDR) machinery.

Illicit DNA repair at telomeres results in cell cycle arrest and end-to-end chromosomal fusions or other improper recombinations causing genome instability. The abrogation of the shelterin assembly or subunit removal decompacts the telomere and causes DDR accumulation. Defects in the shelterin complex are associated with telomere-related pathologies such as cancer and aging.

The supra-structure of the mammalian shelterin complex remains unknown.

Therefore, we lack fundamental knowledge regarding its organization and function.The shelterin complex also acts as a signalling hub, recruiting accessory factors that participate in telomere homeostasis and maintenance; and shelterin subunits are subjected to posttranslational modifications (i.e., ubiquitination, phosphorylation, SUMOylation); however, the functional role of these modifications is not fully understood.

The overarching aim of this project is to solve the atomic structure of the human shelterin complex by cryo-EM and elucidate the molecular events of telomere biology during the cell cycle combining cellular and proteomic approaches.

The outcomes will provide the first structure of the shelterin complex and the shelterin interactome, which will allow to understand defects underlying pathology at molecular level and join this information to physiologic and phenotypic data.

This project will have a substantial impact on my career, as new skills in biophysics, structural biology and proteomic techniques on human macromolecular complexes will complement my previous expertise in X-ray crystallography, biophysics, and biochemistry on bacterial and viral proteins.