Inter-Fork Strand Annealing: a novel mechanism that causes genomic deletions during the termination of DNA replication

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Before a cell divides it has to replicate its genetic material so that each new daughter cell can receive a copy. This process of DNA replication occurs in the S-phase of the cell cycle and is performed by complex protein machines, which are assembled onto DNA at chromosomal sites known as replication origins. These machines unwind the DNA double helix to form "fork" structures, at which the copying occurs. During the S-phase, origins "fire" each releasing a pair of "replication forks" that travel in opposite directions away from their site of initiation. DNA replication is completed when forks from adjacent origins merge. Problems that occur during both the initiation and elongation phases of replication are well known to cause chromosomal alterations and catastrophic mutations that are instrumental in the ageing process, and in the development of age related diseases such as cancer. However, very little is known about the mutagenic potential of replication termination, when replication forks merge. Unlike replication initiation, replication termination can occur at any site in the genome and this makes it difficult to study. My laboratory has pioneered the use of site-specific replication fork barriers to focus termination at specific chromosomal locations. Using this approach we have discovered a novel process by which deletions of chromosomal DNA can occur during replication termination. The aim of this project is to determine exactly how these deletions arise, and the various factors that govern their occurrence. Deletions of chromosomal DNA erode the genetic information that is vital for maintaining the health and function of cells. By understanding the mechanisms that cause these deletions, and the factors that influence their frequency, we will be better placed in the future to assess an individual's capacity for healthy ageing, and to devise measures for assuaging the worst effects of the ageing process.