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

Hamsanathan, Shruthi
; 
Anthonymuthu, Tamil
; 
Han, Suhao
; 
Shinglot, Himaly
; 
Siefken, Ella
; 
Sims, Austin
; 
Sen, Payel
; 
Pepper, Hannah L.
; ; 
Bayir, Hulya
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Journal article
Date
2022-02-16
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Center for Metabolic Disease Research (Temple University)
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Cardiovascular Sciences
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http://hdl.handle.net/20.500.12613/9371
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PepperEtAl-JournalArticle-2022-02.pdf
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http://dx.doi.org/10.1126/sciadv.abl6083
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 b-oxidation and drives a global loss of fat depots. This metabolic shift to b-oxidation gen-erates 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.
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Citation
Shruthi Hamsanathan et al. ,Integrated -omics approach reveals persistent DNA damage rewires lipid metabolism and histone hyperacetylation via MYS-1/Tip60.Sci. Adv.8,eabl6083(2022).DOI:10.1126/sciadv.abl6083
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American Association for the Advancement of Science (AAAS)
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Science Advances, Vol. 8, Iss. 7
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