REPLISTRESS
Financiado
DNA Replication From Physiology to Replication Stress in Human Cancer
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 b...
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.
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Duración del proyecto: 75 meses
Fecha Inicio: 2018-06-26
Fecha Fin: 2024-09-30
Fecha Fin: 2024-09-30
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2024-09-30
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2017-ADG:
ERC Advanced Grant
Cerrada
hace 7 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
UNIVERSITE DE GENEVE
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
201.83K€ |
Participante