The DNA in our cells is packaged by association with proteins, including histones, to form chromatin. The structure of chromatin is regulated by modifications and remodelling enzymes to dynamically allow access to the DNA during cellular activities such as replication, transcription, and repair. Alterations in chromatin structure and composition can have profound and heritable, or epigenetic, effects.
We are investigating how chromatin, or epigenetic regulation, impacts on genome stability. Areas that we have focused on include understanding how chromatin structure and its regulation directly influences DNA repair, chromosome segregation, and DNA replication.
By understanding more about these pathways, we can not only generate mechanistic insights into cellular functions, but also identify novel therapeutic targets and biomarkers for the treatment of cancer.
The SWI/SNF complexes. From Harrod, Lane and Downs, DNA Repair 2020.
A major focus of the lab is the SWI/SNF family of chromatin remodelling complexes. This family is made up of a number of multisubunit complexes that have been shown to be important for maintaining genome stability (for review, see Harrod, Lane and Downs, DNA Repair 2020). Work from our lab and others identified multiple different mechanisms by which SWI/SNF remodellers do this, such as DNA double strand break repair, sister chromatid cohesion, and DNA damage checkpoints.
Notably, genes encoding SWI/SNF subunits are also mutated in human cancers with striking frequency. For example, approximately 40% of clear cell renal cell cancers have deleterious mutations in the PBRM1 subunit of SWI/SNF. We performed a meta-analysis of SWI/SNF misregulation in cancer (in Harrod, Lane, and Downs, DNA Repair 2020) and found that around 20% of cancers have inactivating mutations in SWI/SNF encoding genes. When amplifications are also considered, almost 30% of cancers – across a wide range of cancer types – have misregulation of at least one SWI/SNF subunit.
Our research is aimed at exploring two major areas. First, we want to gain a deeper understanding of the functions of SWI/SNF complexes and of what happens when subunits are missing or misregulated. These studies are particularly focused on SWI/SNF activities that impact on genome stability, but we also look at other functions that can shed light on how SWI/SNF biology changes in cancer cells. Second, we want to identify vulnerabilities of cells with SWI/SNF misregulation that we can use to develop new therapeutic strategies for patients with SWI/SNF deficient cancers.