SWI/SNF-family remodelers (BAF/PBAF in mammals) are essential chromatin regulators, and mutations in human BAF/PBAF components are associated with ∼20% of cancers. Cancer-associated missense mutations in human BRG1 (encoding the catalytic ATPase) have been characterized previously as conferring loss-of-function. Here, we show that cancer-associated missense mutations in BRG1, when placed into the orthologous Sth1 ATPase of the yeast RSC remodeler, separate into two categories: loss-of-function enzymes, or instead, gain-of-function enzymes that greatly improve DNA translocation efficiency and nucleosome remodeling in vitro. Our work identifies a structural “hub,” formed by the association of several Sth1 domains, that regulates ATPase activity and DNA translocation efficiency. Remarkably, all gain-of-function cancer-associated mutations and all loss-of-function mutations physically localize to distinct adjacent regions in the hub, which specifically regulate and implement DNA translocation, respectively. In vivo, only gain-of-function cancer-associated mutations conferred precocious chromatin accessibility. Taken together, we provide a structure-function mechanistic basis for cancer-associated hyperactivity.

SWI/SNF 家族重塑因子（哺乳动物中的 BAF/PBAF）是重要的染色质调节因子，人类 BAF/PBAF 成分的突变与约 20% 的癌症相关。人类BRG1 （编码催化 ATP 酶）中与癌症相关的错义突变先前已被定性为导致功能丧失。在这里，我们表明，当将BRG1中与癌症相关的错义突变放入酵母 RSC 重塑剂的直系同源 Sth1 ATP 酶中时，可分为两类：功能丧失酶，或者相反，功能获得酶可大大改善DNA 易位效率和体外核小体重塑。我们的工作确定了一个由多个 Sth1 结构域联合形成的结构“中心”，可调节 ATP 酶活性和 DNA 易位效率。值得注意的是，所有功能获得性癌症相关突变和所有功能丧失性突变在物理上都定位于中枢中不同的相邻区域，分别专门调节和实现 DNA 易位。在体内，只有与癌症相关的功能获得性突变才赋予染色质的早熟可及性。总而言之，我们为癌症相关的多动症提供了结构功能机制基础。