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Content archived on 2024-05-29

Genes that control human DNA replication


We study the process of chromosome duplication, which ensures that a copy of the entire genome can be passed to each of the daughter cells during mitosis. The molecular mechanisms for the synthesis of new DNA chains are evolutionary conserved between prokaryotes and eukaryotes, but the regulation of chromosomal replication is more complex in the latter. A large group of genes have been identified that control DNA replication in yeast and metazoa. Most of them encode proteins known as "initiators" that are responsible for selecting and activating the genomic regions that serve as "origins of replication". One of their presumed functions is the recruitment and assembly of DNA helicases and DNA polymerases to the chromatin.

With this project we seek to characterize several human initiators, using a combination of genetic and biochemistry techniques. The function of genes such as ORC1 (encoding the large subunit of the origin recognition complex, ORC), CDC6 (encoding an ORC1-related gene), and MCM2-7 (six genes encoding the subunits of a potential DNA helicase) will be assessed in human cells by RNAi-mediated "loss of function" assays. The study will be extended to other initiators such as GINS, a protein complex identified in yeast that remains uncharacterised in mammalian cells. Besides the anticipated roles of these initiators in DNA replication, they may be involved in the cellular responses to different types of DNA damage. Interference with DNA replication increases the frequency of chromosome instability in model systems. Therefore, "replicational stress" in mammalian cells could be a driving force of tumorigenesis.

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