LAUSR

Eukaryotic DNA is wrapped in nucleosomes, which impede the access of transcription factors and regulatory proteins to template DNA. Chromatin remodelers utilize the energy from ATP hydrolysis to drive histone movement relative to nucleosomal DNA and nucleosome editing. Thus, they play critical roles in transcription, DNA replication, and damage repair, and their dysfunctions are often associated with diseases including cancers (Klages-Mundt et al., 2018). Chromatin remodelers can be generally categorized into INO80, SWI/SNF, CHD, and ISWI subfamilies, which share conserved catalytic ATPasetranslocase motors. However, how other auxiliary components of these multi-subunit machinery control their genomic recruitment and actions of DNA translocation remains as a major challenge of the field. Recent structural and biochemical studies provide ground-breaking insights on how multi-subunit chromatin remodelers engage with nucleosomes and their acting mechanisms (Aramayo et al., 2018; Ayala et al., 2018; Knoll et al., 2018; Willhoft et al., 2018). A common theme emerged from these studies is that a remodeler complex tends to make multiple contacts with nucleosomes in order to properly couple its ATPase activity with nucleosome mobilization activities: (i) the motor domains of many remodelers share a common nucleosomal binding site at the superhelical location +2 (SHL+2), which locates two helical turns away from the nucleosome dyad axis (Aramayo et al., 2018; Ayala et al., 2018; Knoll et al., 2018; Willhoft et al., 2018); (ii) closely related INO80 and SWR1 both use an Arp module (Arp5/Ies2 in INO80; Arp6/Swc6 in SWR1) to grab DNA at the opposite sites of nucleosome comparing to the motor domain and also bind to the acidic patch of the histone globular domain (Ayala et al., 2018; Eustermann et al., 2018; Willhoft et al., 2018). These contacts provide an anchor point for remodelers to harness torsional tension generated through DNA translocation to disrupt histone–DNA interactions (Clapier et al., 2017), which in turn trigger subsequent nucleosome mobilization and/or potential histone editing (Willhoft et al., 2018). Using Cryo-EM and subunit deletion analysis of the native yeast INO80 complex, the current structural study by Zhang et al. (2018) revealed exciting new insights on INO80 submodule assembly and a key functional switch that coordinates its remodeling activity. A working model of how the INO80 complex interacts with nucleosomes emerged from these studies is summarized in Figure 1. The catalytic subunit Ino80 serves as a center scaffold to nucleate complex assembly: its insertion motif binds to Rvb1/2 hexamer module, which links the Arp5 module that contacts nucleosomes at the SHL−3 position; unlike SWR1 and other Snf2-like translocase domains, the motor domain of Ino80 targets to SHL−6; the helicaseSANT associated domain (HSA) of Ino80 forms a stable submodule with Arp8/ actin/Apr4, which binds to the linker DNA. Unlike studies based on the INO80 core complex, the intact native INO80 complex used by Zhang et al. (2018) allowed the first visualization of the Nhp10 module, which is