Project description
Chromatin interactions at the telomeres
Telomeres, the protective ends of eukaryotic chromosomes, are essential for genome stability and are maintained by the shelterin complex. Shelterin safeguards telomeres by regulating length, masking chromosome ends and coordinating replication. However, the dynamics and physiological consequences of the interaction of shelterin with nucleosomes remain poorly understood. With the support of the Marie Skłodowska-Curie Actions programme, the ShelChromTelo project aims to elucidate how shelterin binds to telomeric chromatin and influences nucleosome organisation, telomere stability and the telomeric proteome. Researchers will investigate the regulatory mechanisms of shelterin-chromatin interplay throughout the cell cycle. The insights gained could inform future therapeutic strategies targeting shelterin in cancer.
Objective
The linear ends of eukaryotic chromosomes are formed by telomeres, nucleoprotein structures containing double-stranded TTAGGG repeats, ending in a single-stranded DNA 3-overhang. In mammalian cells, the six-subunits Shelterin complex binds telomeres and is critical for telomere homeostasis. Shelterin ensures faithful replication of telomeric DNA, hides linear ends in a looped structure to prevent their recognition as DNA breaks and ensures control over telomere length. Telomeres are packed into nucleosomes, and therefore Shelterin binds in a chromatin context. Interactions between individual Shelterin subunits and nucleosomes have been investigated in vitro, as well as their impact on chromatin organisation. Despite increasing evidence of a Shelterin-chromatin interplay, many questions remain unanswered. The dynamics, affinities and consequences of full Shelterin complex binding to chromatin are unknown. I will employ single-molecule experiments with optical tweezers and bulk assays to monitor the binding of Shelterin on telomeric chromatin and its impact on nucleosomes (and vice versa). The physiological role of this interplay, as well as its regulation, is also largely unknown. I will investigate the impact of an impaired Shelterin-chromatin interaction on telomere and genome stability, as well as its impact on the telomeric proteome and the epigenetic landscape of telomeres. Lastly, I will examine how the Shelterin-chromatin interaction is regulated during the cell cycle.
Altogether, this work will provide fundamental new knowledge on Shelterin recruitment and functions at telomeres. Considering that in recent years Shelterin gained interest as an anti-cancer therapeutic target, this basic knowledge has the potential to guide future research aimed at targeting Shelterin for induction of telomeres dysfunction in cancer cells.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins proteomics
- natural sciences biological sciences genetics DNA
- medical and health sciences clinical medicine oncology
- natural sciences biological sciences genetics chromosomes
- medical and health sciences basic medicine physiology homeostasis
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
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Call for proposal
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(opens in new window) HORIZON-MSCA-2024-PF-01
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NW1 1AT London
United Kingdom
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