One-carbon metabolism enzyme Ahcy is a redox sensor that modulates gene expression to protect against light stress-induced retinal degeneration

Stanhope, S. C.; Singhal, K.; Morato, N. M.; Feng, Y.; Meng, G.; Marlin, M. N.; Kotanko, C. C.; Jarrett, M. M.; Mesecar, A. D.; Cooks, R. G.; Weake, V. M.

doi:10.1101/2025.04.25.650714

bioRxiv · 10.1101/2025.04.25.650714

One-carbon metabolism enzyme Ahcy is a redox sensor that modulates gene expression to protect against light stress-induced retinal degeneration

Stanhope, S. C.·Singhal, K.·Morato, N. M.·Feng, Y.·Meng, G.·Marlin, M. N.·Kotanko, C. C.·Jarrett, M. M.·Mesecar, A. D.·Cooks, R. G.·Weake, V. M.

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Abstract

One-carbon metabolism influences gene expression by providing methyl units for DNA, RNA, and histone methylation. Robust methylation requires rapid hydrolysis of the methylation by-product S-adenosylhomocysteine (SAH) by S-adenosylhomocysteinase (Ahcy). Here, we show Ahcy is a redox-sensitive enzyme that is inhibited by oxidation of a conserved cysteine, C195, in vitro and in vivo. Transient oxidation of Ahcy is neuroprotective in a Drosophila light stress model where it results in rapid gene expression changes and protects against retinal degeneration. Thus, redox sensing by the one-carbon metabolic enzyme Ahcy enables rapid changes in gene expression in response to changes in redox homeostasis.

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Stanhope, S. C., Singhal, K., Morato, N. M., Feng, Y., Meng, G., Marlin, M. N., Kotanko, C. C., Jarrett, M. M., Mesecar, A. D., Cooks, R. G., Weake, V. M.. 2025-04-27. One-carbon metabolism enzyme Ahcy is a redox sensor that modulates gene expression to protect against light stress-induced retinal degeneration. https://doi.org/10.1101/2025.04.25.650714

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