Mechanisms Regulating Genome Replication

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All cells contain a complete copy of the organism's DNA, the genetic blueprint of life, packaged into discrete units called chromosomes. Since new cells need a copy of the genetic material, the chromosomes must be completely and accurately replicated before the cell can divide. Eukaryotes, such as yeast and people, have large genomes with millions of bases encoding the genetic information. To ensure complete replication of these genomes within the allowed time, the process of DNA replication starts at multiple sites along each chromosome, called replication origins. These replication origins are specialised DNA sequences that assemble the cellular machinery that then moves along the DNA, reading and copying the genetic material. It is essential that the cell activates sufficient replication origins to ensure complete replication of the chromosomes. The importance of controlling replication origin activation is highlighted by the genome instability and diseases that may result from uncontrolled chromosome replication. Despite the importance of DNA replication origins we understand little about the DNA sequences that specify and control them. Failures in the processes of DNA replication lead to genetic instability and diseases such as cancer and congenital disorders. In the future, a better understanding of the basic biology that ensures genetic integrity will give new insights that will allow improved diagnosis and treatment of these diseases.We aim to understand how replication origin activation time is controlled. To study this process we have compared genome replication in different organisms. Primarily we work with baker's yeast, since this is safe, cheap and ethical, but most importantly all the steps of genome replication are similar between baker's yeast and people. Therefore advances we make working with yeasts will be informative for future studies and treatment of people. Recently we have found that the patterns of genome replication are very similar in different yeast species (in evolutionary terms equivalent to comparing people with birds). These comparisons allowed us to discover individual replication origins that show dramatic differences in activity between the yeast species. Now we will investigate what is responsible for this difference in origin activation time between the two species. Our experiments suggest that DNA 'regulatory' sequences close to the origin are responsible. Now we want to find these sequences and determine how they alter the activation time of the replication origin.The similarities between genome replication in yeast and people mean that the discovery of these regulatory sequences in yeast may be informative about how replication origin activation time is regulated in people. If too few replication origins activate, parts of the genome will fail to replicate and this can result in cancer and developmental diseases. Therefore, in the future, a better understanding of how replication origin activation time is regulated may allow the development of improved treatments for these diseases.