Format

Send to

Choose Destination
Nucleic Acids Res. 2015 Feb 18;43(3):1646-58. doi: 10.1093/nar/gku1405. Epub 2015 Jan 27.

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

Author information

1
Section of Molecular Biology, Division of Biological Sciences, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0347, USA.
2
Department of Anatomy and Cell Biology, Health Science Center, University of Florida, Gainesville, FL 32610-0235, USA.
3
Section of Molecular Biology, Division of Biological Sciences, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0347, USA lpillus@ucsd.edu.

Abstract

Catalytically active proteins with divergent dual functions are often described as 'moonlighting'. In this work we characterize a new, chromatin-based function of Lys20, a moonlighting protein that is well known for its role in metabolism. Lys20 was initially described as homocitrate synthase (HCS), the first enzyme in the lysine biosynthetic pathway in yeast. Its nuclear localization led to the discovery of a key role for Lys20 in DNA damage repair through its interaction with the MYST family histone acetyltransferase Esa1. Overexpression of Lys20 promotes suppression of DNA damage sensitivity of esa1 mutants. In this work, by taking advantage of LYS20 mutants that are active in repair but not in lysine biosynthesis, the mechanism of suppression of esa1 was characterized. First we analyzed the chromatin landscape of esa1 cells, finding impaired histone acetylation and eviction. Lys20 was recruited to sites of DNA damage, and its overexpression promoted enhanced recruitment of the INO80 remodeling complex to restore normal histone eviction at the damage sites. This study improves understanding of the evolutionary, structural and biological relevance of independent activities in a moonlighting protein and links metabolism to DNA damage repair.

PMID:
25628362
PMCID:
PMC4330366
DOI:
10.1093/nar/gku1405
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center