Cancer-Associated Gain-of-Function Mutations Activate a SWI/SNF-Family Regulatory Hub.
Cancer-Associated Gain-of-Function Mutations Activate a SWI/SNF-Family Regulatory Hub.
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DOI：
10.1016/j.molcel.2020.09.024
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发表时间：
2020-11-19
期刊：
影响因子：
16
通讯作者：
Cairns BR
中科院分区：
文献类型：
--
作者：
Clapier CR;Verma N;Parnell TJ;Cairns BR
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. Domains flanking and linking the ATPase lobes form a conserved structural hub The hub has two distinct regions, to either regulate or implement DNA translocation Cancer-associated GoF and LoF missense mutations map separately to each region Only GoF mutations increase nucleosome sliding and chromatin accessibility Nucleosome sliding by SWI/SNF-family remodelers involves regulated ATP-dependent DNA translocation. Here, Clapier, Verma et al. reveal a conserved bi-partite integrative regulatory hub within SWI/SNF-family ATPases. Region 1 regulates DNA translocation efficiency and harbors gain-of-function cancer-associated mutations, which increase sliding and chromatin accessibility, whereas region 2 implements DNA translocation, providing structure-function mechanistic insight.
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