Integrated -omics approach reveals persistent DNA damage rewires lipid metabolism and histone hyperacetylation via MYS-1/Tip60

Shruthi Hamsanathan, Tamil Anthonymuthu, Suhao Han, Himaly Shinglot, Ella Siefken, Austin Sims, Payel Sen, Hannah L Pepper, Nathaniel W Snyder, Hulya Bayir, Valerian Kagan, Aditi U Gurkar

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Although DNA damage is intricately linked to metabolism, the metabolic alterations that occur in response to DNA damage are not well understood. We use a DNA repair-deficient model of ERCC1-XPF in Caenorhabditis elegans to gain insights on how genotoxic stress drives aging. Using multi-omic approach, we discover that nuclear DNA damage promotes mitochondrial β-oxidation and drives a global loss of fat depots. This metabolic shift to β-oxidation generates acetyl-coenzyme A to promote histone hyperacetylation and an associated change in expression of immune-effector and cytochrome genes. We identify the histone acetyltransferase MYS-1, as a critical regulator of this metabolic-epigenetic axis. We show that in response to DNA damage, polyunsaturated fatty acids, especially arachidonic acid (AA) and AA-related lipid mediators, are elevated and this is dependent on mys-1. Together, these findings reveal that DNA damage alters the metabolic-epigenetic axis to drive an immune-like response that can promote age-associated decline.

Original languageEnglish
Article numbereabl6083
Pages (from-to)eabl6083
JournalScience Advances
Volume8
Issue number7
DOIs
StatePublished - Feb 18 2022

Keywords

  • Animals
  • Caenorhabditis elegans/genetics
  • DNA Damage
  • DNA Repair
  • Histones/metabolism
  • Lipid Metabolism

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