Sirtuin Enzyme Study Offers Clues to Inhibiting Cancer Growth

Researchers at Penn State produced images of a sirtuin enzyme bound to a nucleosome, providing insight into how this enzyme, which helps regulate aging and other metabolic processes, accesses our genetic material to modulate gene expression intracellularly. Sirtuim enzymes are found in organisms ranging from bacteria to humans and are known to play an important role in aging, sensing DNA damage, and suppressing tumors in various cancers. 

In a recent study published in Science Advances, the team visualized a sirtuin enzyme called SIRT6 on its physiologically relevant substrate—the entire nucleosome—and found that it interacts with multiple parts of the nucleosome, not only the histone where the acetyl flag is to be modified.

Using cryo-electron microscopy, the team identified how SIRT6 positions itself on the nucleosome to remove an acetyl group from the K9 position on the histone called H3. The team found that SIRT6 binds to the nucleosome using a type of connection called an “arginine anchor” and forms an inhibitory interaction with the C-terminal tail of histone H2A.

This type of binding is used by various proteins targeting a particularly acidic patch on the nucleosome’s surface. When the SIRT6 arginine anchor was mutated, activity at the K9 position was severely affected, supporting a critical role for the SIRT6’s arginine anchor.

The scientists found that SIRT6 binds to a partially unwrapped nucleosome, with DNA displaced from the end of the nucleosome, which exposes the K56 position. The study provides insights into how SIRT6 can deacetylate both H3 K9 and H3 K56. Understanding how sirtuins interact with the nucleosome to remove the acetyl flag from histones packaged into nucleosomes could inform future drug discovery efforts.