SWI/SNF related ATP-dependent chromatin remodelling complexes act to regulate chromatin accessibility, ensuring that genes are regulated appropriately. Components of the complexes are mutated in approximately 20% of human cancers. PBRM1 is one of defining subunits of the PBAF subtype of SWI/SNF complexes. Additionally, PBRM1 is mutated in approximately 40% of clear cell type renal cell carcinoma (ccRCC). In this study, we characterised the composition of SWI/SNF complexes in ccRCC cells finding that the PBRM1 and SMARCC1 subunits are frequently depleted in ccRCC cell lines. Furthermore, using a ccRCC specific tissue microarray, these subunits are also observed to be depleted at high frequency in tumour tissues. Surprisingly, the proportion of SMARCC1-deficient ccRCC tumours is similar to the well-established ccRCC drivers, VHL and PBRM1 and that more than 40% of ccRCC tumours carried triple deficiencies for PBRM1, SMARCC1, and VHL proteins. The vulnerability of SMARCC1 deficient tumours to SMARCC2 loss was investigated. Unexpectedly, SMARCC1 is upregulated in response to SMARCC2 depletion and undermining the potential for synthetic vulnerability. Proteins that interact with PBRM1 containing complexes were identified by mass spectrometry. Surprisingly, a number of factors related to cell adhesion were identified. These may provide a new insight into the action of PBAF specific forms of SWI/SNF complex.
|Date of Award||2019|
|Supervisor||Tom Owen-Hughes (Supervisor)|