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QLK3-2002-02071
DNA replication and biotechnological applications (REPBIOTECH)
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Contacts
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Quality of Life - 3. The Cell Factory
| Type of Project |
Shared Cost Research |
| Contract No |
QLK3-2002-02071 |
| Total Cost |
|
| EC Contribution |
1,633,468 EUR |
| Start Date |
01-01-2003 |
| Duration |
36 Months |
Abstract
DNA replication is a key process involved in cell division of all living creatures. Based on the
structural and functional homology between archaea and eukaryotes, this project proposes to
co-ordonate efforts of one SME and seven laboratories from five European countries on the
characterisation of DNA replication components, DNA polymerases, accessory proteins, both
in archaea and human. Each step of DNA replication will be investigated, with initiation, elongation
and processing of the lagging strand in order to:
- understand the basic mechanisms at each level.
- isolate novel proteins and enzymes.
- increase the probability of finding new products and key residues.
Two fields of application are concerned: molecular biology products in in vitro amplification
and health with novel DNA replication inhibitors.
Objectives
The project aims at building a European integrated critical mass on DNA replication able to address
the most crucial basic and applied pending questions in this field of life sciences, where competition is
very active between Europe, the USA and Japan. Scientific objectives are:
- The isolation, biochemical and structural characterisation of the main components of the
replication complex;
- To unravel the complexities of the regulation of DNA replication of eukaryotes fundamental to
the understanding of the control of cell proliferation;
- To attempt to determine a minimum in vitro DNA replication complex.
Application objectives are:
- To obtain new DNA polymerases and their accessory factors with high efficiency for long
range PCR, with high fidelity, yield and rapidity;
- To unravel key residues on replication proteins to design new DNA inhibitors.
Activities
The project deals with the evaluation of the potential use of enzymes and accessory factors involved
in DNA replication of hyperthermophilic archaea as novel tools for molecular biology. Based on the
similarity in structures and already demonstrated function complementation between the DNA
replication components in archaea and eukarya (including human), it deals also with contributing to
solve some major problems in DNA replication with potential application in therapeutic strategies.
The project's workplan is divided into nine work packages.
- The first one (WP1) is devoted to management and coordination and deals with all relevant
scientific and administrative aspects of the project.
- The last one (WP9) deals with the potential applications of the results and products obtained
during the course of the project.
- Others are devoted to the various aspects of research proposed in the project according to the
various steps of the DNA replication mechanisms: initiation, elongation and processing of lagging
strand (WP2, WP3, WP4, WP5).
- Since one goal of the project is concerned with the discovery of novel proteins involved in DNA
replication, one specific work package is designed to this end (WP6).
- The resolution of 3-D structures of several proteins and enzymes already available at the starting
date of the current proposal is a critical point for the advancement of the project. Studies on individual
proteins and enzymes are grouped in WP7.
- The final scientific challenge that we propose to address during the course of the project is the
determination of an in vitro replication system, based on hyperthermostable proteins and enzymes
isolated from P. abyssi and/or S. solfataricus (WP8).
Deliverables
The project is expected to produce different types of deliverables.
- basic knowledge on the different steps of replication will cover simultaneously, for
archaea and human, identification of novel components involved in initiation of replication, elongation
and maturation of Okazaki fragments, mechanistic aspects through protein-protein interactions and
structural properties of some key enzymes and proteins selected for their importance (MCM, RF-C).
- Interactions of archaeal components with human components and functional and structural
consequences.
- Results of experiments, published in peer-reviewed journals.
- A second type of deliverables encompasses results and products worth patenting either
because they improve substantially the state of the art in DNA amplification in vitro (PCR
or isothermal amplification) or open novel avenues for DNA replication inhibition.
- The last type of deliverable is related to general information on the project and includes
developing a dedicated website.
Contacts
Coordinator
Participant
