Cel Telomeres are specialised nucleoprotein structures that protect chromosome ends from degradation and promiscuous DNA repair activities. Critically short telomeres give rise to Dyskeratosis Congenita and Hoyeraal-Hreidarrson Syndrome (HHS), highlighting the clinical importance of maintaining telomeres. Telomeres also progressively shorten with each cell division, eventually triggering cellular senescence. Although telomerase is able to extend telomeres to solve the “end replication problem”, its re-expression is a major route to cancer cell immortalization. Hence, telomeres and telomerase must be subject to exquisite regulation to maintain telomere homeostasis and organismal function. We have previously implicated the Fe-S helicase RTEL1 in maintaining vertebrate telomeres, which is frequently mutated in HHS. In this ERC proposal, we will employ proteomic methods, super-resolution microscopy, biochemistry and genetic approaches to: i) investigate why telomerase is the cause of telomere dysfunction in the absence of Rtel1, ii) how RTEL1 is controlled during the cell cycle, and iii) how this process is compromised by Rtel1 mutations in HHS. By establishing quantitative PICh to interrogate telomere composition in unprecedented detail, we have uncovered an unappreciated compensation between RTEL1 and ATRX at telomeres and also identified SLX4IP as a key regulator of telomere recombination, which we will characterize at a mechanistic level. We will extend our expertise in quantitative PICh and genome-wide CRISPR screens to identify novel factors that respond to or are lost from telomeres as a result of: i) induction of DNA damage at telomeres, ii) inhibition of p97 segregase, and iii) the onset of senescence. Our proposal will lead to a greater understanding of the causes/consequences of telomere dysfunction in multiple contexts, the factors that mitigate these effects to maintain telomere homeostasis and how these processes are compromised in human diseases. Dziedzina nauki natural sciencesbiological sciencesgeneticsDNAnatural sciencesphysical sciencesopticsmicroscopysuper resolution microscopymedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticschromosomesmedical and health sciencesbasic medicinephysiologyhomeostasis Słowa kluczowe Telomeres DNA repair homologous recombination Program(-y) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Temat(-y) ERC-2016-ADG - ERC Advanced Grant Zaproszenie do składania wniosków ERC-2016-ADG Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-ADG - Advanced Grant Instytucja przyjmująca THE FRANCIS CRICK INSTITUTE LIMITED Wkład UE netto € 2 118 431,00 Adres 1 MIDLAND ROAD NW1 1AT London Zjednoczone Królestwo Zobacz na mapie Region London Inner London — West Camden and City of London Rodzaj działalności Research Organisations Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Uczestnictwo w unijnych programach w zakresie badań i innowacji Opens in new window sieć współpracy HORIZON Opens in new window Koszt całkowity € 2 118 431,00 Beneficjenci (1) Sortuj alfabetycznie Sortuj według wkładu UE netto Rozwiń wszystko Zwiń wszystko THE FRANCIS CRICK INSTITUTE LIMITED Zjednoczone Królestwo Wkład UE netto € 2 118 431,00 Adres 1 MIDLAND ROAD NW1 1AT London Zobacz na mapie Region London Inner London — West Camden and City of London Rodzaj działalności Research Organisations Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Uczestnictwo w unijnych programach w zakresie badań i innowacji Opens in new window sieć współpracy HORIZON Opens in new window Koszt całkowity € 2 118 431,00