Project description
Telomerase-protecting shelterings as a novel anticancer target
Telomeres are structures at the chromosome ends critical for genome stability. Shelterin, or telosome, is a protein complex protecting telomeres in eukaryotic cells from DNA repair mechanisms and regulating telomerase activity. Recent studies show that components of the shelterin complex mutated in cancer. The EU-funded SHELTERINS project attempts to establish a comprehensive strategy and set of tools to conduct a fundamental investigation on the role of shelterin in cancer. The project's researchers were first in describing shelterin mutations in cancer and presented the idea of targeting shelterin as an anticancer strategy to induce length-independent telomere damage. In the current proposal, they will use mouse models, developing an approach to block the ability of cancer cells to divide indefinitely, effectively impairing cancer growth.
Objective
Telomeres are protective structures at the chromosome ends essential for genome stability. Telomere biology is intricately linked with human cancer. Most cancer cells reactivate telomerase to avoid telomere loss associated to cell division. Targeting telomerase inhibition in cancer has shown very limited efficacy, alternative or additional mechanisms of telomere maintenance are thus at play in cancer. Recent evidence shows that components of the telomere-protecting shelterin complex are mutated in cancer. Shelterin prevents chromosome fusions, impedes persistent DNA damage response at telomeres and regulates telomerase activity. We were first in describing shelterin mutations in cancer and pioneered the idea of targeting shelterin as an anticancer strategy to induce length-idependent telomere damage. We also found that key cancer pathways regulate shelterin function throughout post-transcriptional modifications.
Developing new therapeutic approaches based on targeting shelterin is hampered by lack of mouse models and incomplete understanding of which underlying mechanisms mutations in shelterin drive tumour development. We strive to establish a comprehensive set of tools, to enable us to conduct a fundamental and far-reaching experimental programme on the role of shelterin in cancer. Our specific aims are to i) generate knock-in mice to understand the role of POT1 shelterin mutations found in cancer and develop personalized therapeutic strategies based on these alterations, ii) generate knock-in mice to understand the role of post-translational modifications of the TRF1 shelterin by several cancer pathways for the identification of new cancer targets, and iii) dissect the potential role of TRF1 in cancer stem cells. We expect to block the ability of cancer cells to divide indefinitely and effectively impair cancer growth. Our research programme will reveal the role of two fundamental aspects of biology, telomere capping and chromosomal stability, in cancer.
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Funding Scheme
ERC-ADG - Advanced GrantHost institution
28029 Madrid
Spain