Cancer-Associated Gain-of-Function Mutations Activate a SWI/SNF-Family Regulatory Hub

Abstract

Highlights d Domains flanking and linking the ATPase lobes form a conserved structural hub d The hub has two distinct regions, to either regulate or implement DNA translocation d Cancer-associated GoF and LoF missense mutations map separately to each region d Only GoF mutations increase nucleosome sliding and chromatin accessibility

Sophisticated Conversations between Chromatin and Chromatin Remodelers, and Dissonances in Cancer

“…An elegant in-depth mechanistic analysis of CHD4, using cancer-associated missense mutations transposed into the Drosophila homologue Mi-2, revealed heterogeneous defects (i.e., reduction in protein stability, disruption of DNA binding, and loss of ATPase activity or coupling), leading mainly to loss-of-function [ 258 ], nicely supported by structural work [ 72 ]. However, one CHD4 cancer-associated mutation located in the Brace-I helix (H1196Y) leads to a gain in remodeling efficiency [ 258 ], a result remarkably consistent with that of a similarly located mutation (K938A) introduced in BRG1/Sth1, a SWI/SNF-subfamily remodeler ATPase [ 14 ], strongly suggesting a conserved regulatory function for this region across remodelers from different subfamilies. Of note, the dedifferentiation of triple-negative breast cancer cells is driven in part by the activation of the NuRD remodeler via a MUC1-C (oncogenic mucin 1 C-terminal subunit)-MYC pathway [ 259 ].…”

“…In yeast, the Remodels the Structure of Chromatin (RSC) complex, has served as a model for understanding how nucleosome ejection versus sliding are chosen and conducted. Interestingly, the choice of remodeling outcome relies on the regulation of the DNA translocation efficiency by the conserved and essential Actin Related Proteins (ARP), which are bound to the HSA domain of the ATPase, and a regulatory hub that physically associates the domains flanking and separating the ATPase lobes [ 14 , 34 , 35 ] (see Section 4.6 ). Notably, nucleosome ejection might also occur by spooling DNA off of the adjacent nucleosome via DNA translocation [ 36 , 37 , 38 , 39 ].…”

“…In yeast RSC and SWI/SNF remodelers, it associates Arp7 and Arp9 (along with Rtt102) and is implicated in the critical regulation of coupling, a measurement of DNA translocation efficiency, which drives the capability to achieve nucleosome ejection instead of sliding [ 34 , 35 ]. Moreover, the function of this HSA-bound ARP module is directly related to the regulatory role of the conserved structural hub, a physical multi-component bridge between the lobes, formed by the association of domains flanking and separating the lobes in the SWI/SNF-subfamily remodelers [ 14 ]. Here, biochemical and structural observations strongly support that the efficiency (the optimization of the conversion of the ATP binding and hydrolysis into DNA translocation), the synchronization of the lobes, and their grip on DNA are influenced by the position of the regulatory hub—which is guided itself by the position of the ARP module, and governed by the nucleosomal information collected by all the lobes of the substrate recognition module.…”

“…They are functionally characterized as missense loss-of-function mutations as they lead to reduced or abrogated ATPase and remodeling activities, and decreased DNA accessibility [ 79 , 279 , 280 , 281 ]. In contrast, rare cancer mutations, located in a specific region of the conserved structural hub that bridges the two ATPase lobes, act as missense gain-of-function mutations as they increase DNA translocation efficiency, remodeling activities, and DNA accessibility [ 14 ].…”

“…The precise step in which the inorganic phosphate (Pi) is released is unknown. Model inspired from Reference [ 13 ] and modified to incorporate results and observations from References [ 14 , 15 ], leading to an updated model in which lobe 1 is the stationary lobe. ( C ) Mechanistic and regulatory contacts between remodelers and nucleosomes.…”