Objective
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.
Fields of science
Call for proposal
ERC-2012-ADG_20120314
See other projects for this call
Funding Scheme
ERC-AG - ERC Advanced GrantHost institution
1165 Kobenhavn
Denmark