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PreprintCited by 30Genetics, Aging, and Longevity in Model OrganismsEpigenetics and DNA MethylationDNA Repair Mechanisms

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Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60

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Hamsanathan, Shruthi, Anthonymuthu, Tamil, Mullett, Steven J., Wendell, Stacy G., Han, Suhao, Shinglot, Himaly, Siefken, Ella, Sims, Austin, Sen, Payel, Pepper, Hannah L, Snyder, Nathaniel W., Bayir, Hulya, Kagan, Valerian, Gurkar, Aditi U.·2021·Science Advances
DOI 10.1101/2021.06.24.449832PMC PMC8849393

Preprint — published as 10.1126/sciadv.abl6083 · Paper page

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Abstract

Nuclear DNA damage is intricately linked to cellular metabolism. However, the underlying mechanisms and full range of metabolic alterations that occur in response to persistent DNA damage are not well understood. Here, we use a DNA repair-deficient model of ERCC1-XPF in Caenorhabditis elegans (C. elegans) , that accumulates physiologically relevant, endogenous DNA damage, to gain molecular insights on how persistent genotoxic stress drives biological aging. Using an integrated multi-omic approach, we discover that persistent genotoxic stress rewires lipid metabolism. In particular, nuclear DNA damage promotes mitochondrial β-oxidation and leads to a global loss of fat depots. This metabolic shift to β-oxidation generates acetyl-CoA and drives histone hyperacetylation. Concomitantly, we observe an associated change in gene expression of immune-effector and cytochrome (CYP) genes. We identify MYS-1, the ortholog of mammalian histone acetyltransferase TIP60, as a critical regulator of this metabolic-epigenetic axis. Moreover, we show that in response to persistent DNA damage, polyunsaturated fatty acids (PUFAs), especially arachidonic acid (AA) and AA-related lipid mediators are elevated. This elevation of PUFA species requires mys-1 /Tip60. Together, these findings reveal that persistent nuclear DNA damage alters the metabolic-epigenetic axis to drive an immune-like response that can promote age-associated decline.

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Metadata

Authors
Hamsanathan, S., Anthonymuthu, T., Mullett, S. J., Wendell, S. G., Han, S., Shinglot, H., Siefken, E., Sims, A., Sen, P., Pepper, H. L., Snyder, N. W., Bayir, H., Kagan, V., & Gurkar, A. U.
Affiliations
  • University of Pittsburgh (US)
  • National Institutes of Health (US)
  • National Institute on Aging (US)
Corresponding author
Gurkar, Aditi U.
ORCID
Venue
Science Advances
Publisher
openRxiv
Published
2021-06-24
Volume
8
Issue
7
Pages
eabl6083-eabl6083
ISSN
2375-2548 (ISSN-L)
DOI
10.1101/2021.06.24.449832
PMC
PMC8849393
OpenAlex
W4213004890
Cited by
30
References
1
Citations by year
2026: 6 · 2025: 7 · 2024: 10 · 2023: 3 · 2022: 4
FWCI
2.01
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Science Advances (publishedVersion, cc-by-nc)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • TUScholarShare (Temple University) (submittedVersion, cc-by-nc)
Funders
  • National Institutes of Health (1s10od023402-01a1, HL114453, AI068021, NS061817, P40OD010440)
  • National Institute on Aging (R00AG049126, ZIAAG000679)
  • National Heart, Lung, and Blood Institute (P01HL114453)
  • National Cancer Institute (R01CA165065, R01CA243142, P30CA047904)
  • National Institute of General Medical Sciences (R01GM132261, R01GM113908)
  • National Institute of Allergy and Infectious Diseases (U19AI068021, U01AI156924, U01AI156923, R01AI145406)
  • National Institute of Neurological Disorders and Stroke (R01NS061817, R37NS061817, R01NS076511)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
DNA damage, lipid metabolism, histone hyperacetylation, Tip60, histone acetyltransferase, mitochondrial beta-oxidation, acetyl-CoA, aging, Caenorhabditis elegans, fat depots, arachidonic acid, polyunsaturated fatty acids, lipid mediators
MeSH terms
Animals, DNA Damage, DNA Repair, Histones, Caenorhabditis elegans, Lipid Metabolism

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