‘Structural aneuploidy’ - deletions, amplifications and translocations of chromosome segments - is a characteristic of many cancers and can potentially be caused by defective regulation of DNA replication. DNA replication occurs in two strictly non-overlapping phases: first, replication origins are ‘licensed’ for replication and then during S phase, the CDK and DDK kinases promotes initiation at licensed origins. Deregulation of this process can lead to amplification of chromosomal segments (if replicated DNA is relicensed) or deletions (if an insufficient number of origins are used).
The aim of the project is to understand how cells normally prevent over- or under-replication of chromosome segments. The basic experimental part of the programme will use Xenopus egg extracts, which provide a strong base for understanding the basic biochemistry of genome stability pathways, and human tissue culture cell lines, where the role and importance of different pathways can be explored. We will apply this basic research to understanding the development of oesophageal cancer, which shows very high levels of structural aneuploidy.