Multivalent binding of the tardigrade Dsup protein to chromatin promotes yeast survival and longevity upon exposure to oxidative damage

Rhiannon R. Aguilar, Laiba F. Khan, Christopher K. Cummins, Nina Arslanovic, Thea Grauer, Kaylah Birmingham, Kritika Kasliwal, Spike D. L. Posnikoff, Ujani Chakraborty, Allison R. Hickman, Rachel Watson, Ryan J. Ezell, Sabrina R. Hunt, Laylo Mukhsinova, Hannah E. Willis, Martis W. Cowles, Richard Garner, Abraham Shim, J. Ignacio Gutierrez, Bryan J. Venters, Matthew R. Marunde, Brian D. Strahl, Michael-Christopher Keogh () and Jessica K. Tyler ()
Additional contact information
Rhiannon R. Aguilar: Weill Cornell Medicine
Laiba F. Khan: EpiCypher Inc.
Christopher K. Cummins: University of North Carolina at Chapel Hill
Nina Arslanovic: Weill Cornell Medicine
Thea Grauer: Weill Cornell Medicine
Kaylah Birmingham: Weill Cornell Medicine
Kritika Kasliwal: Weill Cornell Medicine
Spike D. L. Posnikoff: Weill Cornell Medicine
Ujani Chakraborty: Weill Cornell Medicine
Allison R. Hickman: EpiCypher Inc.
Rachel Watson: EpiCypher Inc.
Ryan J. Ezell: EpiCypher Inc.
Sabrina R. Hunt: EpiCypher Inc.
Laylo Mukhsinova: EpiCypher Inc.
Hannah E. Willis: EpiCypher Inc.
Martis W. Cowles: EpiCypher Inc.
Richard Garner: Weill Cornell Medicine
Abraham Shim: Weill Cornell Medicine
J. Ignacio Gutierrez: Weill Cornell Medicine
Bryan J. Venters: EpiCypher Inc.
Matthew R. Marunde: EpiCypher Inc.
Brian D. Strahl: University of North Carolina at Chapel Hill
Michael-Christopher Keogh: EpiCypher Inc.
Jessica K. Tyler: Weill Cornell Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Tardigrades are remarkable in their ability to survive extreme environments. The damage suppressor (Dsup) protein is thought to contribute to their extreme resistance to reactive oxygen species (ROS) generated by irradiation. Here we show that expression of Ramazzottius varieornatus Dsup in Saccharomyces cerevisiae reduces oxidative DNA damage and extends lifespan in response to chronic oxidative genotoxicity. Dsup uses multiple modes of engagement with the nucleosomal H2A/H2B acidic patch, H3/H4 histone tails and DNA to bind across the yeast genome without bias. Effective chromatin binding and genome protection requires the Dsup HMGN-like motif and C-terminal sequences. These findings give precedent and mechanistic understanding for engineering an organism by physically shielding its genome to promote survival and longevity in the face of oxidative damage.

Date: 2025
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DOI: 10.1038/s41467-025-63652-3

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