SIRT2 Reverses 4-Oxononanoyl Lysine Modification on Histones

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Biology

Background:

• Post-translational modifications (PTMs) are vital for protein function and biological processes.
• Lysine 4-oxononanoylation (4-ONylation) is a recently identified histone PTM that inhibits nucleosome assembly during oxidative stress.
• The enzymes responsible for reversing 4-ONylation remain unidentified, limiting research into its cellular roles.

Purpose of the Study:

• To identify cellular enzymes capable of removing 4-ONyl modifications from histones.
• To elucidate the mechanism by which 4-ONylation is reversed.
• To understand the role of SIRT2 in oxidative stress and 4-ONylation.

Main Methods:

• In vitro assays to test SIRT2 activity on 4-ONylated proteins.
• Crystal structure determination of SIRT2 in complex with a 4-ONyl peptide.
• Cellular experiments to validate SIRT2's role in 4-ONylation removal.

Main Results:

• Mammalian SIRT2 was identified as an enzyme that removes 4-ONyl modifications from histones and other proteins in live cells.
• The crystal structure revealed a key lone pair-π interaction between Phe119 and the ketone oxygen of the 4-ONyl group.
• This study provides the first evidence of a mechanism for reversing 4-ONyl lysine modification.

Conclusions:

• SIRT2 plays a critical role in reversing lysine 4-oxononanoylation.
• The findings offer insights into SIRT2's function in oxidative stress response pathways.
• This work facilitates further investigation into the biological significance of 4-ONylation.