Cel Replication of the genome is of critical importance for cell proliferation and organismal development. To ensure accurate and complete replication of their genome, eukaryotes have hundreds to thousands of replication origins. In budding yeast, the genomic positions of all the origins are known, as is the order in which they fire. In contrast, in human cells, the mapping of origins is controversial and origin firing may be stochastic and plastic. Furthermore, while normal cells replicate their genomes with high fidelity; in cancer cells, the presence of activated oncogenes leads to collapse of DNA replication forks (DNA replication stress), DNA damage and genomic instability.My laboratory has recently elucidated key differences in DNA replication after oncogene induction. We mapped replication origins on the human genome and found that, in addition to the origins present before oncogene induction, a new class of “oncogene-induced” origins was observed upon activation of the CCNE1 (Cyclin E) or MYC (c-Myc) genes. Only forks from the oncogene-induced origins were prone to collapse, leading to the genomic instability patterns observed in the common human cancers.In this proposal, we aim to map with high precision the human replication origins, determine if their firing is stochastic or deterministic and identify sequence motifs that are important for origin firing (Aim 1). We further aim to explore how transcription in the G1 phase of the cell cycle regulates origin firing (Aim 2). This endeavour is motivated by our observation that transcription in G1 inactivates intragenic origins. Finally, we aim to understand how transcription, replication and repair are coordinated to avoid DNA replication stress in normal cells (Aim 3).The proposed experiments will help us understand how normal cells replicate their genome with high fidelity and how oncogenes interfere with this process. Dziedzina nauki natural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologymedical and health sciencesbasic medicinephysiologynatural sciencesbiological sciencesgeneticsgenomes Słowa kluczowe DNA replication origins break-induced replication fork collapse fork repair Program(-y) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Temat(-y) ERC-2017-ADG - ERC Advanced Grant Zaproszenie do składania wniosków ERC-2017-ADG Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-ADG - Advanced Grant Instytucja przyjmująca UNIVERSITE DE GENEVE Wkład UE netto € 2 231 378,00 Adres RUE DU GENERAL DUFOUR 24 1211 Geneve Szwajcaria Zobacz na mapie Region Schweiz/Suisse/Svizzera Région lémanique Genève Rodzaj działalności Higher or Secondary Education Establishments 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 € 2 231 378,00 Beneficjenci (1) Sortuj alfabetycznie Sortuj według wkładu UE netto Rozwiń wszystko Zwiń wszystko UNIVERSITE DE GENEVE Szwajcaria Wkład UE netto € 2 231 378,00 Adres RUE DU GENERAL DUFOUR 24 1211 Geneve Zobacz na mapie Region Schweiz/Suisse/Svizzera Région lémanique Genève Rodzaj działalności Higher or Secondary Education Establishments 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 € 2 231 378,00
