A moonlighting metabolic protein influences repair at DNA double-stranded breaks

Area of Science:

• Molecular Biology
• Biochemistry
• Yeast Genetics

Background:

• Moonlighting proteins exhibit multiple distinct functions.
• Lys20, known as homocitrate synthase (HCS), is involved in lysine biosynthesis.
• Lys20 also functions in DNA damage repair through interaction with Esa1.

Purpose of the Study:

• To characterize the chromatin-based DNA repair function of Lys20.
• To elucidate the mechanism by which Lys20 suppresses DNA damage sensitivity in esa1 mutants.
• To explore the link between metabolic enzymes and DNA repair pathways.

Main Methods:

• Utilized LYS20 mutants defective in lysine biosynthesis but active in repair.
• Analyzed chromatin landscape and histone acetylation in esa1 mutant cells.
• Investigated Lys20 recruitment to DNA damage sites and its effect on INO80 complex.

Main Results:

• Lys20 is recruited to DNA damage sites.
• Overexpression of Lys20 enhances the recruitment of the INO80 remodeling complex.
• Lys20 promotes normal histone eviction at DNA damage sites, restoring function in esa1 mutants.
• Demonstrated a link between lysine metabolism and DNA repair.

Conclusions:

• Lys20 possesses a novel chromatin-based function in DNA repair.
• Lys20's role in DNA repair involves facilitating histone eviction via the INO80 complex.
• This work highlights the evolutionary and biological significance of moonlighting proteins, connecting metabolism to DNA repair.