title: Functions for diverse metabolic activities in heterochromatin.
abstract: Growing evidence demonstrates that metabolism and chromatin dynamics are not separate processes but that they functionally intersect in many ways. For example, the lysine biosynthetic enzyme homocitrate synthase was recently shown to have unexpected functions in DNA damage repair, raising the question of whether other amino acid metabolic enzymes participate in chromatin regulation. Using an in silico screen combined with reporter assays, we discovered that a diverse range of metabolic enzymes function in heterochromatin regulation. Extended analysis of the glutamate dehydrogenase 1 (Gdh1) revealed that it regulates silent information regulator complex recruitment to telomeres and ribosomal DNA. Enhanced N-terminal histone H3 proteolysis is observed in GDH1 mutants, consistent with telomeric silencing defects. A conserved catalytic Asp residue is required for Gdh1's functions in telomeric silencing and H3 clipping. Genetic modulation of α-ketoglutarate levels demonstrates a key regulatory role for this metabolite in telomeric silencing. The metabolic activity of glutamate dehydrogenase thus has important and previously unsuspected roles in regulating chromatin-related processes.
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0347;
authors.forename: Xue Bessie
authors.initials: XB
authors.lastname: Su
authors.affiliation: Section of Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0347; UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093 lpillus@ucsd.edu.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Pillus
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D020868:Gene Silencing; D018086:Glutamate Dehydrogenase (NADP+) / Q000235:genetics / Q000378:metabolism*; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D007656:Ketoglutaric Acids / Q000378:metabolism; D008969:Molecular Sequence Data; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism
chemical_list: D006570:Heterochromatin; D006657:Histones; D007656:Ketoglutaric Acids; D029701:Saccharomyces cerevisiae Proteins; D038281:Silent Information Regulator Proteins, Saccharomyces cerevisiae; C519119:JHD2 protein, S cerevisiae; D056484:Jumonji Domain-Containing Histone Demethylases; C000609733:GDH1 protein, S cerevisiae; D018086:Glutamate Dehydrogenase (NADP+); C087778:SIR2 protein, S cerevisiae; D056565:Sirtuin 2
keywords: SIR complex; epigenetic silencing; glutamate dehydrogenase; metabolism; yeast chromatin