King's College London

The CRUK Discovery Programme Foundation Award supports multidisciplinary research that aims to develop or apply novel technologies and methodologies to address difficult questions in cancer. Dr Pavri’s project, ‘Assessing DNA replication timing as a vulnerability in cancer,’ will take place over a six-year period.

DNA replication happens during cell division and is when a cell makes a copy of its DNA before the cell divides. Dr Pavri and his team will be looking at how the timing of DNA replication affects a type of genetic damage called chromosomal translocations - where pieces of the thread-like structures that carry genetic information (called chromosomes) break off and attach to other chromosomes. They are a common feature of many cancers and can contribute to tumour progression by disrupting the normal control of genes that regulate cell growth.

In B cells (immune cells that produce antibodies to fight infection), these DNA rearrangements occur as an undesired collateral damage of the normal process of producing protective antibodies. But if the translocations disrupt genes that usually prevent tumour growth, it can contribute to the development of B cell cancers like Burkitt lymphoma and diffuse large B cell lymphoma.

In previous research, Dr Pavri and his team discovered that the timing of DNA replication appears to influence whether these rearrangements occur, finding that early DNA replication of certain genes makes them more likely to develop cancer-causing DNA rearrangements.

They also identified specific regions of DNA that help control when genes are copied during DNA replication. By deleting these regions of DNA, the team were able to prevent early replication timing and translocations of these genes, without altering gene expression – suggesting that it may be possible to prevent translocations from occurring without compromising the growth and survival of the cell. However, it is not yet fully understood what controls replication timing or how it drives translocations.

In this project, Dr Pavri and his team aim to identify the factors that regulate early DNA replication, and explore how these factors contribute to DNA translocations, using CRISPR-engineered B cells and genomics analyses. They will also use preclinical models to test whether the factors they identify directly contribute to the formation of these translocations.

The team anticipates that the study will lay the groundwork for future research by providing the evidence and understanding needed to support larger preclinical studies and future funding applications. In the longer term, this could help pave the way for a new approach to cancer treatment. They also plan to ensure the data, research materials and computational tools they develop are available to the research community.