ATP-dependent chromatin remodelers are commonly mutated in human cancer. Mammalian SWI/SNF complexes comprise three conserved multisubunit chromatin remodelers (cBAF, ncBAF and PBAF) that share the BRG1 (also known as SMARCA4) subunit responsible for the main ATPase activity. BRG1 is the most frequently mutated Snf2-like ATPase in cancer. In the present study, we have investigated the role of SWI/SNF in genome instability, a hallmark of cancer cells, given its role in transcription, DNA replication and DNA-damage repair. We show that depletion of BRG1 increases R-loops and R-loop-dependent DNA breaks, as well as transcription–replication (T-R) conflicts. BRG1 colocalizes with R-loops and replication fork blocks, as determined by FANCD2 foci, with BRG1 depletion being epistatic to FANCD2 silencing. Our study, extended to other components of SWI/SNF, uncovers a key role of the SWI/SNF complex, in particular cBAF, in helping resolve R-loop-mediated T-R conflicts, thus, unveiling a new mechanism by which chromatin remodeling protects genome integrity.

ATP 依赖性染色质重塑剂通常在人类癌症中发生突变。哺乳动物 SWI/SNF 复合物包含三个保守的多亚基染色质重塑物（cBAF、ncBAF 和 PBAF），它们共享负责主要 ATP 酶活性的 BRG1（也称为 SMARCA4）亚基。BRG1 是癌症中最常发生突变的 Snf2 样 ATP 酶。在本研究中，我们研究了 SWI/SNF 在基因组不稳定性中的作用，这是癌细胞的一个标志，因为它在转录、DNA 复制和 DNA 损伤修复中的作用。我们表明 BRG1 的消耗增加了 R 环和 R 环依赖的 DNA 断裂，以及转录-复制 (TR) 冲突。BRG1 与 R 环和复制叉块共定位，由 FANCD2 病灶确定，BRG1 耗尽对 FANCD2 沉默是上位性的。我们的研究扩展到 SWI/SNF 的其他组成部分，