Specific binding modes of SIRT6 C-terminal domain to the nucleosome core particle influence DNA unwrapping and H3K27 accessibility

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Abstract
Sirtuins are a class of NAD-dependent histone deacetylases that regulate important biological pathways in prokaryotes and eukaryotes. This enzyme family comprises seven members, named SIRT1 to SIRT7. Among them, Sirtuin 6 (SIRT6) is a human sirtuin that deacetylates histones and plays a key role in DNA repair, telomere maintenance, carbohydrate and lipid metabolism, and lifespan. SIRT6’s structure consists of a zinc finger domain, a Rossmann fold domain containing the NAD+ binding site, and disordered N-terminal and C-terminal (CTD) extensions. The specific role of the CTD on SIRT6 interaction with nucleosomes for histone deacetylation remains unclear. Here, we resort to extended molecular dynamics simulations to uncover the dynamical behavior of the full-length SIRT6 bound to a nucleosome core particle. Our simulations reveal that the CTD preferentially interacts with DNA at the entry/exit near the enzyme’s docking site, exhibiting a variety of different binding modes. In specific cases, the CTD participates to the promotion of DNA unwrapping and promotes H3K27 accessibility to SIRT6’s active site, suggesting a pivotal role of this domain for H3K27 deacetylation. This work provides new structural insights into the binding process of the full-length SIRT6 to a nucleosome core particle, shedding light on the conformational behavior and functional role of its CTD. It constitutes an important step towards the understanding of SIRT6 deacetylation mechanisms and specificity.
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