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

Hamsanathan, S.; Anthonymuthu, T.; Mullet, S. J.; Han, S.; Shinglot, H.; Siefken, E.; Sims, A. A.; Sen, P.; Pepper, H. L.; Wendell, S. G.; Snyder, N. W.; Bayir, H.; Kagan, V. E.; Gurkar, A. U.

doi:10.1101/2021.06.24.449832

bioRxiv · 10.1101/2021.06.24.449832

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

Hamsanathan, S.·Anthonymuthu, T.·Mullet, S. J.·Han, S.·Shinglot, H.·Siefken, E.·Sims, A. A.·Sen, P.·Pepper, H. L.·Wendell, S. G.·Snyder, N. W.·Bayir, H.·Kagan, V. E.·Gurkar, A. U.

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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 {beta}-oxidation and leads to a global loss of fat depots. This metabolic shift to {beta}-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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Hamsanathan, S., Anthonymuthu, T., Mullet, S. J., Han, S., Shinglot, H., Siefken, E., Sims, A. A., Sen, P., Pepper, H. L., Wendell, S. G., Snyder, N. W., Bayir, H., Kagan, V. E., Gurkar, A. U.. 2021-06-24. Persistent DNA damage rewires lipid metabolism and promotes histone hyperacetylation via MYS-1/Tip60.. https://doi.org/10.1101/2021.06.24.449832

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