Abstract
SummarySWI/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.
Highlights
Chromatin remodeling involves the use of ATP-dependent complexes, termed remodelers, to move, restructure, and/or eject nucleosomes—the basic unit of chromatin structure (Becker and Workman, 2013; Clapier and Cairns, 2014; Clapier et al, 2017)
Our results identify a new category of gain-offunction cancer-associated missense mutations and define a conserved SWI/SNF-family integrative structural hub with two distinct regions: one that regulates remodeler efficiency and another required for implementing remodeling—via the coupling of ATP hydrolysis into DNA translocation
A System to Characterize the Sth1 Structural Hub and Gain-of-Function Mutations To understand how the Sth1 structural hub regulates DNA translocation, and to determine whether certain cancer-associated missense mutations in BRG1 create gain-of-function nucleosome remodeling activities, we introduced into STH1 25 alanine substitutions, and 11 cancer-associated missense mutations (Tate et al, 2019) (Figures 1B and 1C)
Summary
Chromatin remodeling involves the use of ATP-dependent complexes, termed remodelers, to move, restructure, and/or eject nucleosomes—the basic unit of chromatin structure (Becker and Workman, 2013; Clapier and Cairns, 2014; Clapier et al, 2017). Remodelers occupy gene enhancers, promoters, and coding regions to regulate nucleosome occupancy and positioning, and impact the ability of transcription factors and regulators to bind DNA within chromatin (Clapier and Cairns, 2014; Lorch and Kornberg, 2015). Mutations in subunits of remodelers are present in $20% of human cancers and in a wide array of specific developmental disorders/syndromes (Helming et al, 2014; Kadoch et al, 2013; Shain and Pollack, 2013; Sokpor et al, 2017). Missense mutations are of the highest interest, given the potential for gain-of-function and/or dominant-negative mutations
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