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Genes that control human DNA replication

Final Activity Report Summary - DNAREPLICA (Genes that control human DNA replication.)

DNA replication is the central process by which a cell makes a full copy of its chromosomes before division, in order to pass one entire genome to each one of the two daughter cells. This process is controlled by a group of proteins called 'initiators' that bind to specific sequences in the DNA called 'replication origins'. Initiators are capable of unwinding the DNA double helix and orchestrate the assembly of 'replisomes', macromolecular structures that contain all the enzymes required for DNA synthesis.

This project aimed at understanding the mode of action of several initiator proteins using (a) human cells in culture and (b) genetically modified mice. A second goal was to explore the possibility of using the detection of initiator proteins in cancer diagnosis.

The main experimental achievements are summarised below:
- The main function of initiator proteins ORC ('origin recognition complex') and CDC6 ('cell division cycle 6') is to attract MCM2-7 (mini-chromosome maintenance 2-7) protein complexes to the DNA.
- MCM2-7 complexes associate with additional proteins (CDC45 and GINS) and the resultant complex is likely capable of unwinding the DNA double helix.
- MCM2-7 complexes are critical to maintain genomic integrity, especially under conditions of 'replicative stress', e.g. when cells have to copy their genome in the presence of DNA damaging agents.
- Genetically modified mice strains have been generated, (a) to express abnormally high levels of CDC6; (b) to eliminate the expression of MCM3 in an inducible manner. These strains will be very valuable to study the process of DNA replication in vivo.
- Antibodies directed to MCM2-7 or the GINS complex are excellent proliferation markers and may be useful in cancer diagnosis. Though some of the specific objectives of Dr Fialips' MC IRG project have not yet been reached, her reintegration into the European scientific community is a great success. She now holds a permanent academic position at Newcastle University where she is transferring her knowledge and expertise. She is leading several research projects in the field of clay sciences, including a project with industry, and she is involved in several international collaborations.