Chd1 uses exit DNA as a molecular brake to regulate chromatin remodeling

Chromatin remodelers are ATP-dependent motor proteins that dynamically reorganize chromatin architecture, playing essential roles in gene expression, development, and immune function. Dysregulation of these enzymes is associated with various diseases, including cancer, developmental disorders, and metabolic syndromes. Among them,  chromodomain-helicase-DNA-binding protein 1 (Chd1) is known for maintaining regular nucleosome spacing, but how it senses and responds to DNA configuration has remained unclear.

In a recent study published in Life Metabolism, Professor Zhucheng Chen’s team at Tsinghua University revealed cryo-electron microscopy (cryo-EM) structures of yeast Chd1-nucleosome complexes in both ADP and stable ATP analogue ADP·BeF_x-bound states, simulating different steps of the ATPase cycle.

The team found that Chd1 induces two conformations of exit DNA: a fully wrapped state and a partially unwrapped state. Surprisingly, the unwrapped DNA conformation inhibits Chd1’s activity by locking its ATPase motor in a closed, inactive conformation. A key player in this regulation is the exit-DNA-binding loop (EDBL), a positively charged motif in Chd1 that directly binds to unwrapped exit DNA (Figure 1). Mutating the EDBL weakened this interaction, lifting the inhibition and enabling continued DNA translocation.

This mechanism acts as a molecular brake, allowing Chd1 to sense the structural state of exit DNA and adjust its remodeling activity accordingly. Unlike other remodelers such as Snf2 and ISWI, which display coordinated domain movements during their ATPase cycles, Chd1 remains locked in a closed conformation in the ADP-bound state due to its interaction with the unwrapped DNA. Supporting evidence of biochemical assays and single-molecule FRET (smFRET) experiments confirmed that DNA unwrapping suppresses Chd1 activity not by physically blocking it, but through allosteric signaling that modulates its conformation.

This study proposes a new mechanism by which Chd1 senses and responds to DNA unwrapping via EDBL engagement to suppress translocation. This self-regulating mechanism ensures proper nucleosome spacing and chromatin organization. The findings provide new insights into how chromatin remodelers integrate structural cues to fine-tune their activity, with implications for epigenetic regulation and potential therapeutic targeting of chromatin-associated diseases.