Contribution of SWI/SNF chromatin remodelling complexes to DNA damage responses and genome stability

Background - The SWI/SNF chromatin remodelling complexes are of central importance in cancer biology.

There is evidence that misregulation of SWI/SNF subunits contributes to the genesis or progression of cancer, and strikingly, misregulation is apparent in approximately one third of human cancer samples.

While the contribution of SWI/SNF misregulation to cancer is evident, the underlying reasons for this remain imperfectly defined. There are two factors that help explain this uncertainty. First, there are dozens of different SWI/SNF complexes, characterised by diverse subunit and paralogue combinations.

Second, these complexes perform multiple different cellular roles that each have the potential to influence the development or progression of cancer.

These roles encompass regulation of gene expression, as well as activities that impact on genome stability, such as DNA repair, replication stress responses, and promoting normal centromere structure and function.

Aims and Methods - Here, we propose to elucidate cancer-relevant functions of SWI/SNF complexes through four strategic objectives.

In Aim 1, we will address the fundamental question: which functions of SWI/SNF complexes are important for preventing the development or progression of cancer?

We will do this by performing separation of function screens, which will provide us with an unprecedented map of SWI/SNF functionality.

In Aim 2, using cell and molecular biology approaches, we will explore mechanisms by which SWI/SNF influences genome stability by understanding how SWI/SNF influences the chromatin binding dynamics of 53BP1 and cohesin proteins.

In the third aim, we will investigate an understudied set of paralogues present in SWI/SNF complexes; namely SMARCD1, 2 and 3.

Building on evidence that their expression patterns change in response to irradiation or to perturbation of other SWI/SNF subunits, we will explore how these paralogues contribute to SWI/SNF functions.

We will interrogate therapeutic vulnerabilities of SWI/SNF deficient cancers in the final aim, drawing on the evidence generated in the other aims to fully exploit the defects associated with SWI/SNF misregulation in cancer.

How the results of this research will be used - Collectively, these studies will address multiple fundamental questions surrounding the role of SWI/SNF complexes in cancer and offer insights into how this knowledge can be most effectively used in clinical settings.