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DDRegulation Report Summary

Project ID: 616236
Funded under: FP7-IDEAS-ERC
Country: Denmark

Mid-Term Report Summary - DDREGULATION (Regulation of DNA damage responses at the replication fork)

The precise and complete replication of cellular DNA during each cell cycle is vital for the transmission of genetic information and for cell and organism survival. However, DNA replication integrity is constantly challenged by endogenous and exogenous genotoxic sources that compromise the stability and progression of replication forks, the sites at which the DNA replication process takes place. In particular, the slowing or stalling of replication forks, a potentially deleterious condition generally referred to as replication stress, is a major driver of genomic instability that may lead to cancer and other severe pathologies. This project aims to comprehensively explore and characterize the protective regulatory signaling processes operating directly in the context of replication forks in response to DNA damage and related perturbations in vertebrate cells. To achieve this, we developed a groundbreaking new method for systems-wide identification of the proteins that function directly in the context of sites of DNA damage and replication stress, allowing for comprehensive dissection of the cellular pathways that respond to and overcome these insults. Using this methodology, we have identified a range of previously unrecognized components of replication stress and DNA damage responses, thus revealing important new molecular insights into cellular genome stability maintenance pathways. Modification of multiple proteins within this network by the small modifier protein ubiquitin plays a key role in replication stress responses, but this involvement is incompletely understood and has not yet been systematically explored. In the next phase of this project, we therefore aim to utilize and extend the above methodology to specifically monitor and functionally characterize, for the first time, the landscape of ubiquitin-dependent signaling processes acting locally in the vicinity of stressed replication forks. If successful, these studies will allow unprecedented new disease-relevant insights into the molecular mechanisms and biological functions of the cellular signaling responses that protect the integrity of the genetic material in the face of perturbations to the DNA replication process.

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