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DYNACOM Report Summary

Project ID: 281851
Funded under: FP7-IDEAS-ERC
Country: Greece

Final Report Summary - DYNACOM (From Genome Integrity to Genome Plasticity: Dynamic Complexes Controlling Once per Cell Cycle Replication)

A millions new cells are born in our body every second. Every one of these cells must ensure that it passes down an accurate copy of its genome to its daughter cells. Accurate genome duplication is controlled by dynamic multi-subunit protein complexes which associate with DNA and dictate when and where replication should take place. Defects in these complexes lead to re-replication of the genome across evolution and have been linked to DNA-replication stress and tumorigenesis.

Our work advanced our understanding of how once per cell cycle replication is normally controlled within the context of the living cell and how defects in this control may result in loss of genome integrity and provide genome plasticity. To this end, live cell imaging in human cells in culture was combined with genetic studies and in silico modelling and analysis of the behaviour of dynamic protein complexes maintaining genome stability in time and space.

The main outcomes of this project are:
1. We unraveled novel pathways operating in normal cells which ensure timely genome replication and link cell cycle control to DNA damage responses and cell fate decisions. By combining functional live-cell imaging to modeling, we showed that licensing DNA for replication must be controlled in multiple steps during the G1 phase of the cell cycle to avoid replication stress, and identified rate limiting factors which direct timely licensing in human cells. We showed that licensing factors link DNA replication to DNA damage responses and ensure accurate DNA repair at different cell cycle stages. We identified licensing regulators as novel factors which connect DNA replication control to cell fate decisions during development and in the adult.
2. We showed that aberrations in the licensing system can provide a selective advantage, through amplification of different loci in fission yeast. To this end, a natural selection experiment was set up. Genetic analysis was used to pinpoint the factors which enhance or inhibit gene amplification following rereplication.
3. We investigated how rereplication may take place along the genome in single cells. By combining modelling of full genome DNA rereplication to analysis of rereplication at the single cell level we showed that there is heterogeneity amongst a rereplicating population, leading to a plethora of different genotypes through genome plasticity.
4. We demonstrated that our findings are relevant for gene amplification events associated with cancer. We showed that ectopic expression of human licensing factors enhances drug resistance due to gene amplification in both cancer and normal cells. This was verified by in silico analysis of cancer specimens. Similarly, lack of licensing control enhances tumor progression in mice. We characterized compounds which interfere with licensing regulation and may have potential as anti-tumor agents.

Genome plasticity leading to cell-to-cell genetic heterogeneity directs cancer evolution. Our findings offer novel insight into mechanisms crucial for cancer development and progression.

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