The Rad53CHK1/CHK2-Spt21NPAT and Tel1ATM axes couple glucose tolerance to histone dosage and subtelomeric silencing - Archive ouverte HAL Access content directly
Journal Articles Nature Communications Year : 2020

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

(1) , (1) , (1) , (2) , (3) , (1) , (4) , (4) , (5) , (3) , (2) , (1, 6)
1
2
3
4
5
6

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.
Fichier principal
Vignette du fichier
s41467-020-17961-4.pdf (2.53 Mo) Télécharger le fichier
Origin : Publication funded by an institution
Loading...

Dates and versions

inserm-02950793 , version 1 (28-09-2020)

Identifiers

Cite

Christopher Bruhn, Arta Ajazi, Elisa Ferrari, Michael Charles Lanz, Renaud Batrin, et al.. The Rad53CHK1/CHK2-Spt21NPAT and Tel1ATM axes couple glucose tolerance to histone dosage and subtelomeric silencing. Nature Communications, 2020, 11 (1), pp.4154. ⟨10.1038/s41467-020-17961-4⟩. ⟨inserm-02950793⟩
125 View
30 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More