Ketones facilitate transcriptional resolution of secondary DNA structures in premature aging

Petr, M. A.; Carmona-Marin, L. M.; Tulika, T.; Kristensen, S.; Reves, S.; Bakula, D.; Keijzers, G.; Osborne, B.; Mitchell, S. J.; Hamilton, S.; Kato, J.; Alfaras, I.; Teklu, A. A.; Heckenbach, I.; Madsen, J.; Ben Ezra, M.; Mkrtchyan, G.; Varner, E.; Fink, B.; von Krusenstiern, E.; Snyder, N. W.; Herranz, H.; de Cabo, R.; Scheibye-Knudsen, M.

doi:10.1101/2022.03.08.483430

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bioRxiv · 10.1101/2022.03.08.483430

Ketones facilitate transcriptional resolution of secondary DNA structures in premature aging

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Abstract

There is currently no established intervention for Cockayne syndrome, a disease characterized by progressive early onset neurodegeneration with features of premature aging. Here, we tested if acetyl-CoA precursors, citrate and beta-hydroxybutyrate, could reduce features of Cockayne syndrome in three model systems. We identified the gene Helicase 89B as a homologue of CSB in drosophila and found that the ketone beta-hydroxybutyrate rescued features of premature aging in Hel89B deficient flies. In mammals, loss of the citrate carrier Indy exacerbated the phenotype of Csbm/m mice which was rescued by a ketogenic diet. The rescue effect appeared to be mediated through ketone stimulated histone acetylation and facilitation of transcriptional readthrough of secondary DNA structures. These findings link a ketogenic diet with transcriptional resolution of secondary structures and DNA repair.

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Petr, M. A., Carmona-Marin, L. M., Tulika, T., Kristensen, S., Reves, S., Bakula, D., Keijzers, G., Osborne, B., Mitchell, S. J., Hamilton, S., Kato, J., Alfaras, I., Teklu, A. A., Heckenbach, I., Madsen, J., Ben Ezra, M., Mkrtchyan, G., Varner, E., Fink, B., von Krusenstiern, E., Snyder, N. W., Herranz, H., de Cabo, R., Scheibye-Knudsen, M.. 2022-03-09. Ketones facilitate transcriptional resolution of secondary DNA structures in premature aging. https://doi.org/10.1101/2022.03.08.483430

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