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The role of essential DNA metabolism genes in vertebrate chromosome replication

Objective

Faithful chromosomal DNA replication is essential to maintain genome stability. A number of DNA metabolism genes are involved at different levels in DNA replication. These factors are thought to facilitate the establishment of replication origins, assist the replication of chromatin regions with repetitive DNA, coordinate the repair of DNA molecules resulting from aberrant DNA replication events or protect replication forks in the presence of DNA lesions that impair their progression. Some DNA metabolism genes are present mainly in higher eukaryotes, suggesting the existence of more complex repair and replication mechanisms in organisms with complex genomes. The impact on cell survival of many DNA metabolism genes has so far precluded in depth molecular analysis. The use of cell free extracts able to recapitulate cell cycle events might help overcoming survival issues and facilitate these studies. The Xenopus laevis egg cell free extract represents an ideal system to study replication-associated functions of essential genes in vertebrate organisms. We will take advantage of this system together with innovative imaging and proteomic based experimental approaches that we are currently developing to characterize the molecular function of some essential DNA metabolism genes. In particular, we will characterize DNA metabolism genes involved in the assembly and distribution of replication origins in vertebrate cells, elucidate molecular mechanisms underlying the role of essential homologous recombination and fork protection proteins in chromosomal DNA replication, and finally identify and characterize factors required for faithful replication of specific vertebrate genomic regions.
The results of these studies will provide groundbreaking information on several aspects of vertebrate genome metabolism and will allow long-awaited understanding of the function of a number of vertebrate essential DNA metabolism genes involved in the duplication of large and complex genomes.

Call for proposal

ERC-2013-CoG
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Host institution

UNIVERSITA DEGLI STUDI DI MILANO
Address
Via Festa Del Perdono 7
20122 Milano
Italy

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Activity type
Higher or Secondary Education Establishments
Principal investigator
Vincenzo Costanzo (Dr.)
Administrative Contact
Annalisa Brengola (Mrs.)
EU contribution
€ 132 000

Beneficiaries (2)

UNIVERSITA DEGLI STUDI DI MILANO
Italy
EU contribution
€ 132 000
Address
Via Festa Del Perdono 7
20122 Milano

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Activity type
Higher or Secondary Education Establishments
Principal investigator
Vincenzo Costanzo (Dr.)
Administrative Contact
Annalisa Brengola (Mrs.)
IFOM-ISTITUTO FONDAZIONE DI ONCOLOGIA MOLECOLARE ETS
Italy
EU contribution
€ 1 867 800
Address
Via Adamello 16
20139 Milano

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Activity type
Research Organisations
Administrative Contact
Carlo Raimondi Cominesi (Mr.)