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From Genome Integrity to Genome Plasticity Dynamic Complexes Controlling Once p...

From Genome Integrity to Genome Plasticity Dynamic Complexes Controlling Once per Cell Cycle Replication Accurate genome duplication is controlled by multi-subunit protein complexes which associate with chromatin and dictate when and where replication should take place. Dynamic changes in these complexes lie at the heart of their abi... ver más

31/01/2017

UNIVERSITY OF PATR...

2M€

Presupuesto del proyecto: 2M€

Líder del proyecto

PANEPISTIMIO PATRON 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 2017-01-31 No tenemos la información de la convocatoria

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1 Participantes

UNIVERSITY OF PATRAS

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Líder del proyecto

PANEPISTIMIO PATRON 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 Accurate genome duplication is controlled by multi-subunit protein complexes which associate with chromatin and dictate when and where replication should take place. Dynamic changes in these complexes lie at the heart of their ability to ensure the maintenance of genomic integrity. Defects in origin bound complexes lead to re-replication of the genome across evolution, have been linked to DNA-replication stress and may predispose for gene amplification events. Such genomic aberrations are central to malignant transformation. We wish to understand 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 will be combined with genetic studies in fission yeast and modelling and in silico analysis. The proposed research aims to: 1. Decipher the regulatory mechanisms which act in time and space to ensure once per cell cycle replication within living cells and how they may be affected by system aberrations, using functional live cell imaging. 2. Test whether aberrations in the licensing system may provide a selective advantage, through amplification of multiple genomic loci. To this end, a natural selection experiment will be set up in fission yeast . 3. Investigate how rereplication takes place along the genome in single cells. Is there heterogeneity amongst a population, leading to a plethora of different genotypes? In silico analysis of full genome DNA rereplication will be combined to single cell analysis in fission yeast. 4. Assess the relevance of our findings for gene amplification events in cancer. Does ectopic expression of human Cdt1/Cdc6 in cancer cells enhance drug resistance through gene amplification? Our findings are expected to offer novel insight into mechanisms underlying cancer development and progression.

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