DARTSin · The Telosome: Deciphering the architecture of the shelterin complex and its network
Horizon Europe — Marie Skłodowska-Curie Actions
- Duration
- 2022-09-01 → 2024-08-31
- EU contribution
- €230,774
- Participants
- 1
- Scheme
- HORIZON-TMA-MSCA-PF-EF
Lines connect the coordinator with its partners.
Results in brief
The Telosome: Deciphering the architecture of the shelterin complex and its network
The ends of eukaryotic chromosomes contain a specialized region named telomere, which must be protected to avoid being falsely recognized as broken DNA. The chief guardian of telomeres is a protein complex called shelterin, which is composed of six protein subunits: TRF1, TRF2, TIN2, Rap1, TPP1 and POT1. Shelterin is a dynamic complex, structurally and in composition, and several subcomplexes can co-exist. Despite many years of research, the overall architecture of shelterin and how shelterin protects the telomere remains unknown. Shelterin regulates telomere biology by interacting with other cellular proteins. Failure in telomere protection is associated with telomere-related pathologies such as cancer and aging, and several mutations on shelterin subunits have been found in cancer cells. This project aims to characterize shelterin and its role in telomere protection and regulation with three research objectives using biochemical, biophysical, and structural biology techniques in combination with proteomics. Overall, this research project focuses on understanding shelterin at molecular and functional levels in the cell, information that helps to understand human illnesses.
Data: CORDIS, © European Union
Project objective
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.
Original text from CORDIS.
Participants
- KOBENHAVNS UNIVERSITET · KOBENHAVNCoordinatorDenmark
Links
- View on CORDIS
- DOI: 10.3030/101065213
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e50f8ce935&appId=PPGMS
- https://ec.europa.eu/research/participants/documents/downloadPublic?documentIds=080166e5f31f1c5e&appId=PPGMS
Data: CORDIS, © European Union