We are interested in how cells regulate recombination in response to replication fork stalling. As part of a collaborative project with the Carr lab we use a regulatable system to study events at stalled replication forks. This system, first developed in the Carr lab (http://www.sussex.ac.uk/lifesci/carrlab/index), enables us to induce replication stalling at a particular site in order to analyse how replication and recombination are coordinated.

We have used this inducible system to study replication stalling within a short palindrome, where the DNA sequence reads the same backwards as forwards, with an axis of symetry in the middle. Recombination-dependent replication restart results in a novel chromosomal rearrangement generating an acentric giant palindrome and a dicentric palindromic chromosome (Mizuno et al, 2009). 25% of cells undergo this rearrangement each S phase resulting in cell death due to chromosome missegregation. Giant palindromes without centromeres are lost during cell division. Dicentric (two centromere) palindromic chromosomes align correctly but then break when the chromosomes segregate at anaphase. These breaks can be repaired by fusion with other chromosomes. Breakage-fusion-breakage cycles are one of the hallmark of cancer cells and thus giant palindromes are potent intermediates in the genomic rearrangements that characterise cancer.