The Rad53CHK1/CHK2-Spt21NPAT and Tel1ATM axes couple glucose tolerance to histone dosage and subtelomeric silencing

Christopher Bruhn,Marco Foiani,Sunil Laxman,Adhish Walvekar,Michael Charles Lanz,Emmanuelle Fabre,Marcus Bustamente Smolka,Elisa Ferrari,Maria Pia Longhese,Ramveer Choudhary,Arta Ajazi,Renaud Batrin

doi:10.1038/s41467-020-17961-4

Abstract

The DNA damage response (DDR) coordinates DNA metabolism with nuclear and non-nuclear processes. The DDR kinase Rad53CHK1/CHK2 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 Spt21NPAT 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 Tel1ATM and Rpd3HDAC 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.

Highlights

The DNA damage response (DDR) coordinates DNA metabolism with nuclear and nonnuclear processes
We have previously found that the glucose-regulated phosphatase PP2A attenuates DDR activity[23]
We tested by semi-quantitative spot assay whether the DDR kinases Mec1ATR, Tel1ATM, Rad53CHK1/CHK2, Chk1CHK1, and Dun[1] were required to survive under glucose limitation. mec1Δ and rad53Δ mutants can be kept alive by deleting the SML1 gene, encoding the ribonucleotide reductase (RNR) inhibitor[19]

Summary

Introduction

The DNA damage response (DDR) coordinates DNA metabolism with nuclear and nonnuclear processes. Together with the relative activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs), Ac-CoA levels influence histone acetylation, chromatin state, and gene expression, coupling metabolic changes to cell cycle control[11,12,13]. This sensing mechanism likely relies on a physiological balance of Ac-CoA vs Ac-CoA acceptors, it is not known whether and to what extent Ac-CoA metabolism is affected by variations in histones as Ac-CoA acceptors. Our data identify independent roles of Rad53-Spt[21] and Tel[1] axes in modulating glucose dependence

Methods

Results

Conclusion