TY - JOUR T1 - The Rad53-Spt21 and Tel1 axes couple glucose tolerance to histone dosage and subtelomeric silencing. JF - Nat Commun Y1 - 2020 A1 - Bruhn, Christopher A1 - Ajazi, Arta A1 - Ferrari, Elisa A1 - Lanz, Michael Charles A1 - Batrin, Renaud A1 - Choudhary, Ramveer A1 - Walvekar, Adhish A1 - Laxman, Sunil A1 - Longhese, Maria Pia A1 - Fabre, Emmanuelle A1 - Smolka, Marcus Bustamente A1 - Foiani, Marco KW - Acetylation KW - Ataxia Telangiectasia Mutated Proteins KW - Cell Cycle Proteins KW - Checkpoint Kinase 2 KW - DNA Damage KW - DNA Repair KW - Gene Silencing KW - Glucose KW - Histone Deacetylases KW - Histones KW - Intracellular Signaling Peptides and Proteins KW - Mutation KW - Phosphorylation KW - Protein-Serine-Threonine Kinases KW - Saccharomyces cerevisiae KW - Saccharomyces cerevisiae Proteins KW - Serine KW - Telomere KW - Transcription Factors AB -

The DNA damage response (DDR) coordinates DNA metabolism with nuclear and non-nuclear processes. The DDR kinase Rad53 controls histone degradation to assist DNA repair. However, Rad53 deficiency causes histone-dependent growth defects in the absence of DNA damage, pointing out unknown physiological functions of the Rad53-histone axis. Here we show that histone dosage control by Rad53 ensures metabolic homeostasis. Under physiological conditions, Rad53 regulates histone levels through inhibitory phosphorylation of the transcription factor Spt21 on Ser276. Rad53-Spt21 mutants display severe glucose dependence, caused by excess histones through two separable mechanisms: dampening of acetyl-coenzyme A-dependent carbon metabolism through histone hyper-acetylation, and Sirtuin-mediated silencing of starvation-induced subtelomeric domains. We further demonstrate that repression of subtelomere silencing by physiological Tel1 and Rpd3 activities coveys tolerance to glucose restriction. Our findings identify DDR mutations, histone imbalances and aberrant subtelomeric chromatin as interconnected causes of glucose dependence, implying that DDR kinases coordinate metabolism and epigenetic changes.

VL - 11 IS - 1 ER -