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bioRxiv · 10.1101/2023.08.09.551721

Cryo-EM structure of DDM1-HELLS chimera bound to nucleosome reveals a mechanism of chromatin remodeling and disease regulation

Nartey, W.·Goodarzi, A. A.·Williams, G. J.
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Abstract

Human HELicase, Lymphoid Specific (HELLS), and plant homolog Deficient in DNA Methylation 1 (DDM1), belong to a distinct class of chromatin remodelers that play important roles in DNA repair, transcription, and maintenance of DNA methylation in heterochromatin. HELLS also promotes the growth of hard-to-treat cancers including glioblastoma and hepatocellular carcinoma. Here, we identify an auto-inhibitory HELLS N-terminal coiled-coil, unravelling a long-standing question of HELLS inactivity in vitro. Using cryo-EM, we determine the 3.5 [A] structure of an active DDM1-HELLS chimera in complex with a nucleosome. The structure reveals that a HELLS-specific insertion in the ATPase lobe 2 interacts with the nucleosome acidic patch to enhance chromatin remodeling. At the C-terminus, we resolve a unique motif, and disease hot spot, that binds and stabilizes the ATPase motor of the HELLS family of remodelers. Finally, we provide mechanistic insights for how post-translational modifications in the motor domain and midloop could modulate HELLS activity to regulate cancer stem cell state.

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Nartey, W., Goodarzi, A. A., Williams, G. J.. 2023-08-09. Cryo-EM structure of DDM1-HELLS chimera bound to nucleosome reveals a mechanism of chromatin remodeling and disease regulation. https://doi.org/10.1101/2023.08.09.551721

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