Integrated -omics approach reveals persistent DNA damage rewires lipid metabolism and histone hyperacetylation via MYS-1/Tip60
Open accessPublished version of a preprint
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Combinatorial patterns of histone acetylations and methylations in the human genome
Wang, Z., Zang, C., Rosenfeld, J. A., Schones, D. E., Barski, A., Cuddapah, S., Cui, K., Roh, T.-Y., Peng, W., Zhang, M. Q., et al. (2008) · Nature Genetics · doi:10.1038/ng.154 · Cited by 2,331 · see citing works
Induction of autophagy by spermidine promotes longevity
Eisenberg, T., Knauer, H., Schauer, A., Büttner, S., Ruckenstuhl, C., Carmona-Gutierrez, D., Ring, J., Schroeder, S., Magnes, C., Antonacci, L., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1975 · Cited by 1,680 · see citing works
The central role of DNA damage in the ageing process
Schumacher, B., Pothof, J., Vijg, J., & Hoeijmakers, J. H. J. (2021) · Nature · doi:10.1038/s41586-021-03307-7 · Cited by 907 · see citing works
Acetyl-CoA and the regulation of metabolism: mechanisms and consequences
Shi, L., & Tu, B. P. (2015) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2015.02.003 · Cited by 903 · see citing works
Cai, L., Sutter, B. M., Li, B., & Tu, B. P. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.05.004 · Cited by 701 · see citing works
Histone acetylation: molecular mnemonics on the chromatin
Gräff, J., & Tsai, L.-H. (2013) · Nature Reviews Neuroscience · doi:10.1038/nrn3427 · Cited by 680 · see citing works
Fatty acid carbon is essential for dNTP synthesis in endothelial cells
Schoors, S., Bruning, U., Missiaen, R., Queiroz, K. C. S., Borgers, G., Elia, I., Zecchin, A., Cantelmo, A. R., Christen, S., Goveia, J., et al. (2015) · Nature · doi:10.1038/nature14362 · Cited by 646 · see citing works
Regulation of autophagy by cytosolic acetyl-coenzyme A
Mariño, G., Pietrocola, F., Eisenberg, T., Kong, Y., Malik, S. A., Andryushkova, A., Schroeder, S., Pendl, T., Harger, A., Niso-Santano, M., et al. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.01.016 · Cited by 500 · see citing works
Mitochondrial dysfunction in ataxia-telangiectasia
Valentin-Vega, Y. A., MacLean, K. H., Tait-Mulder, J., Milasta, S., Steeves, M., Dorsey, F. C., Cleveland, J. L., Green, D. R., & Kastan, M. B. (2012) · Blood · doi:10.1182/blood-2011-08-373639 · Cited by 365 · see citing works
Nuclear Acetyl-CoA Production by ACLY Promotes Homologous Recombination
Sivanand, S., Rhoades, S., Jiang, Q., Lee, J. V., Benci, J., Zhang, J., Yuan, S., Viney, I., Zhao, S., Carrer, A., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.06.008 · Cited by 295 · see citing works
Mueller, M. M., Castells-Roca, L., Babu, V., Ermolaeva, M. A., Müller, R.-U., Frommolt, P., Williams, A. B., Greiss, S., Schneider, J. I., Benzing, T., et al. (2014) · Nature Cell Biology · doi:10.1038/ncb3071 · Cited by 108 · see citing works
Smitherman, A. B., Wood, W. A., Mitin, N., Ayer Miller, V. L., Deal, A. M., Davis, I. J., Blatt, J., Gold, S. H., & Muss, H. B. (2020) · Cancer · doi:10.1002/cncr.33112 · Cited by 80 · see citing works
Chambliss, A. B., Wu, P., Chen, W., Sun, S. X., & Wirtz, D. (2013) · The FASEB Journal · doi:10.1096/fj.12-227108 · Cited by 34 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Inflammation and DNA damage: cause, effect or both
Pezone, A., Olivieri, F., Napoli, M. V., Procopio, A., Avvedimento, E. V., & Gabrielli, A. (2023) · Nature Reviews Rheumatology · doi:10.1038/s41584-022-00905-1 · Cited by 212 · see citing works
- Authors
- Hamsanathan, S., Anthonymuthu, T., 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)
- Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
- Corresponding author
- Gurkar, Aditi U.
- ORCID
- Venue
- Science Advances
- Published
- 2022-02-18
- Volume
- 8
- Issue
- 7
- Pages
- eabl6083-eabl6083
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC8849393
- OpenAlex
- W4213004890
- Cited by
- 30
- References
- 13
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 10 · 2023: 3 · 2022: 4
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- 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, AI145406, AI156924, 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
