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SITE SPECIFIC DNA REPLICATION PERTURBATION AND ITS EFFECTS ON CHROMOSOME SEGREGA...

SITE SPECIFIC DNA REPLICATION PERTURBATION AND ITS EFFECTS ON CHROMOSOME SEGREGATION Challenges to the stable maintenance of the human genome can come from both endogenous and exogenous sources. However, one of the major threats to genome stability occurs during normal DNA metabolism. The genome is particularly su... ver más

31/05/2018

UCPH

2M€

Presupuesto del proyecto: 2M€

Líder del proyecto

KOBENHAVNS UNIVERSITET No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo FP7 notifico la concesión del proyecto el día 2018-05-31 No tenemos la información de la convocatoria

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1 Participantes

UCPH

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Líder del proyecto

KOBENHAVNS UNIVERSITET No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 2M€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto Challenges to the stable maintenance of the human genome can come from both endogenous and exogenous sources. However, one of the major threats to genome stability occurs during normal DNA metabolism. The genome is particularly susceptible to perturbation during the S-phase of the cell cycle when DNA replication occurs. This is because DNA replication forks can encounter chemical adducts, DNA secondary structures, topological constraints or bound proteins that hinder their progression. In actively proliferating cells, such as stem cells, replication perturbation can lead to fork stalling, breakage or collapse. These scenarios can, in turn, generate deleterious chromosomal rearrangements that have the potential to initiate human disease. Despite recent advances in our understanding of the biochemical process of DNA replication, the precise details of the events occurring at sites where replication forks have been perturbed remain poorly characterised. This is because in-depth analysis of the perturbation of replication represents a major technical challenge, principally because adducts and lesions generated by DNA damaging agents are randomly distributed throughout the genome at sites that cannot be controlled or predicted. To overcome this technical limitation, we have developed systems for site-specific perturbation of DNA replication that can be transferred to any locus in any cell type. The aim is to define how replication fork perturbation is detected and engaged by cellular stress-response factors, and then tolerated or repaired. This highly integrated proposal, and the pioneering technologies that will be used to fulfil our ambitious aims, will have significant implications for the understanding not only of replication perturbation and its effects on chromosome dynamics in mitosis, but also of the role of replication stress in the aetiology of cancer and premature ageing. It will open up new horizons both in and across these fields of research.

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