Multivalent interactions drive nucleosome binding and efficient chromatin deacetylation by SIRT6

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• SIRT6 is a protein deacetylase crucial for cellular homeostasis.
• SIRT6 associates with chromatin and reduces global histone H3 acetylation.
• The mechanism by which SIRT6 achieves this chromatin modification is not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanism of SIRT6 interaction with nucleosomes.
• To understand how SIRT6 achieves efficient deacetylation of histones on chromatin.

Main Methods:

• Biochemical analysis of SIRT6-nucleosome interactions.
• Characterization of the 2:1 enzyme:nucleosome complex formation.
• Investigation of the role of the SIRT6 C-terminus in binding affinity.

Main Results:

• SIRT6 forms an exceptionally tight 2:1 complex with nucleosome core particles via asymmetric binding.
• Both SIRT6 molecules bind to the nucleosome acidic patch, with the C-terminus mediating higher affinity binding through DNA recognition.
• Multivalent interactions facilitate productive binding and efficient histone deacetylation.

Conclusions:

• SIRT6's unique ability to tightly interact with nucleosomes is key to its efficient deacetylase activity.
• The described binding mechanism explains how SIRT6 maintains cellular homeostasis through histone deacetylation and transcriptional repression.