SWR1C loss promotes longevity through tRNA-mediated proteostasis

Moreno-Mendez, E.; Meneses-Plascencia, J.; Ulloa-Calzonzin, J.; Salazar-Martinez, I.; Balarezo-Cisneros, L. N.; Sanchez-Puig, N.; Delneri, D.; Oktaba, K.; Funes, S.; DeLuna, A.

doi:10.64898/2025.12.05.692690

bioRxiv · 10.64898/2025.12.05.692690

SWR1C loss promotes longevity through tRNA-mediated proteostasis

Moreno-Mendez, E.·Meneses-Plascencia, J.·Ulloa-Calzonzin, J.·Salazar-Martinez, I.·Balarezo-Cisneros, L. N.·Sanchez-Puig, N.·Delneri, D.·Oktaba, K.·Funes, S.·DeLuna, A.

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Abstract

The conserved SWR1C chromatin remodeling complex promotes cellular aging, yet the mechanisms linking its activity to lifespan control remain poorly defined. Although SWR1C shapes chromatin architecture and regulates non-coding RNA expression, how these activities relate to its role in aging remains unclear. Here, we combine genetic and lifespan-epistasis analyses to identify the cellular processes that underlie SWR1C-dependent chronological longevity in Saccharomyces cerevisiae. Loss of subunits specifically required for H2A.Z deposition robustly extends longevity, and this effect is functionally linked to cytosolic translation and proteostasis pathways. Lifespan profiling of ncRNA deletions reveals a substantial fraction of aging phenotypes and prevalent genetic interactions with SWR1, with tRNAs emerging as key determinants of its long-lived phenotype. The expression of specific tRNA genes is dysregulated in swr1{Delta} cells, and interactions with tyrosine-decoding tRNA genes are linked to ER proteotoxic stress, suggesting that altered tRNA pools affect proteostasis during aging. These findings establish tRNAs as central mediators of SWR1C-associated longevity, revealing a fundamental connection between chromatin remodeling, RNA biology, and proteostasis stress responses in lifespan regulation.

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Moreno-Mendez, E., Meneses-Plascencia, J., Ulloa-Calzonzin, J., Salazar-Martinez, I., Balarezo-Cisneros, L. N., Sanchez-Puig, N., Delneri, D., Oktaba, K., Funes, S., DeLuna, A.. 2025-12-08. SWR1C loss promotes longevity through tRNA-mediated proteostasis. https://doi.org/10.64898/2025.12.05.692690

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