The PBRM1 subunit of the PBAF (SWI/SNF) chromatin remodeling complex is mutated in ∼40% of clear cell renal cancers. PBRM1 loss has been implicated in responses to immunotherapy in renal cancer, but the mechanism is unclear. DNA damage-induced inflammatory signaling is an important factor determining immunotherapy response. This response is kept in check by the G2/M checkpoint, which prevents progression through mitosis with unrepaired damage. We found that in the absence of PBRM1, p53-dependent p21 up-regulation is delayed after DNA damage, leading to defective transcriptional repression by the DREAM complex and premature entry into mitosis. Consequently, DNA damage-induced inflammatory signaling pathways are activated by cytosolic DNA. Notably, p53 is infrequently mutated in renal cancer, so PBRM1 mutational status is critical to G2/M checkpoint maintenance. Moreover, we found that the ability of PBRM1 deficiency to predict response to immunotherapy correlates with expression of the cytosolic DNA-sensing pathway in clinical samples. These findings have implications for therapeutic responses in renal cancer.

中文翻译：

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PBAF 损失通过有缺陷的 G2/M 检查点维护导致 DNA 损伤诱导的炎症信号传导


PBAF (SWI/SNF) 染色质重塑复合物的 PBRM1 亚基在约 40% 的透明细胞肾癌中发生突变。 PBRM1 缺失与肾癌免疫治疗的反应有关，但其机制尚不清楚。 DNA损伤诱导的炎症信号是决定免疫治疗反应的重要因素。这种反应受到 G2/M 检查点的控制，防止有丝分裂中未修复损伤的进展。我们发现，在缺乏 PBRM1 的情况下，p53 依赖性 p21 上调在 DNA 损伤后延迟，导致 DREAM 复合体转录抑制有缺陷并过早进入有丝分裂。因此，DNA 损伤诱导的炎症信号通路被胞质 DNA 激活。值得注意的是，p53 在肾癌中很少发生突变，因此 PBRM1 突变状态对于 G2/M 检查点的维持至关重要。此外，我们发现 PBRM1 缺陷预测免疫治疗反应的能力与临床样本中胞质 DNA 传感通路的表达相关。这些发现对肾癌的治疗反应具有影响。