PBAF loss leads to DNA damage induced inflammatory signalling through defective G2/M checkpoint maintenance

PBRM1 is a subunit of the PBAF (SWI/SNF) chromatin remodelling complex that is mutated in approximately 40% of clear cell renal cell carcinomas (ccRCC). PBRM1 loss has been implicated in the response to immune checkpoint inhibitor (ICI) therapy in ccRCC. However, it is unclear how PBRM1 influences this. DNA damage-induced inflammatory signalling is an important factor determining ICI therapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. Here, we show that PBRM1 is required for p53-dependent maintenance of the G2/M checkpoint. In its absence, p53-dependent transcriptional upregulation of p21 is delayed, leading to defective repression of DREAM complex targets and premature entry into mitosis. Consequently, DNA damage induced inflammatory signalling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in ccRCC, so PBRM1 mutational status is critical to G2/M checkpoint maintenance following DNA damage in this cancer. These findings have implications for ICI therapy responses in ccRCC.