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

Christopher Bruhn (), Arta Ajazi, Elisa Ferrari, Michael Charles Lanz, Renaud Batrin, Ramveer Choudhary, Adhish Walvekar, Sunil Laxman, Maria Pia Longhese, Emmanuelle Fabre, Marcus Bustamente Smolka and Marco Foiani ()
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Christopher Bruhn: The FIRC Institute of Molecular Oncology (IFOM)
Arta Ajazi: The FIRC Institute of Molecular Oncology (IFOM)
Elisa Ferrari: The FIRC Institute of Molecular Oncology (IFOM)
Michael Charles Lanz: Weill Institute for Cell and Molecular Biology, Cornell University
Renaud Batrin: Université de Paris, Laboratoire Génomes, Biologie Cellulaire et Thérapeutiques
Ramveer Choudhary: The FIRC Institute of Molecular Oncology (IFOM)
Adhish Walvekar: Institute for Stem Cell Science and Regenerative Medicine (inStem)
Sunil Laxman: Institute for Stem Cell Science and Regenerative Medicine (inStem)
Maria Pia Longhese: Università degli Studi di Milano-Bicocca
Emmanuelle Fabre: Université de Paris, Laboratoire Génomes, Biologie Cellulaire et Thérapeutiques
Marcus Bustamente Smolka: Weill Institute for Cell and Molecular Biology, Cornell University
Marco Foiani: The FIRC Institute of Molecular Oncology (IFOM)

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17961-4

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