Molecular Mechanisms of DNA Protection by Tardigrade Damage Suppressor Protein (Dsup): Structural Adaptation and Functional Interactions

<p>Ionizing radiation and reactive oxygen species (ROS) pose significant threats to genomic integrity, leading to DNA damage, mutations, and disease. Tardigrades, extremotolerant organisms, exhibit remarkable resilience to such stressors, largely attributed to the DNA damage suppressor protein (Dsup). This study investigates the molecular mechanisms underlying Dsup’s DNA-protective function, focusing on its structural adaptability and interaction with nucleic acids. </p> <p>Using a combination of bioinformatics, biophysical techniques (circular dichroism, NMR, surface plasmon resonance), mass spectrometry, and computational modeling, we demonstrate that Dsup is an intrinsically disordered protein (IDP) with flexible N- and C-terminal regions and a central amphipathic helix forming a helix-turn-helix motif and highly charged C-terminal domain. The C-terminal domain, enriched in positively charged residues, mediates strong electrostatic interactions with DNA, while the helical region stabilizes the complex through structural adaptation. Experimental results confirm that X-ray irradiation did not compromise the integrity or cause additional oxidative damage to free DNA in the presence of Dsup in DNA-protein mixture. These features enable dynamic structural transitions upon DNA binding, forming an electrostatic and hydration-based shield that mitigates hydroxyl radical-induced damage. </p> <p>Our findings provide critical insights into the structure–function relationship of Dsup and its role in genomic protection. Beyond radioprotection, this work highlights the potential vi </p> <p>synergy between Dsup and tardigrade-derived Cytoplasmic Abundant Heat Soluble (CAHS) proteins, which stabilize cellular components under desiccation and thermal stress. Combining Dsup’s DNA shielding with CAHS-mediated structural stabilization could enable innovative strategies for radioprotection, vaccine preservation, and space biology, paving the way for biotechnological applications that enhance resilience in extreme environments. </p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year dc:date.available

2026

Author dc:creator

• Tran, Huy

Contributors dc:contributor

• Innokentiy Maslennikov
• Aftab Ahmed
• Surya Nauli
• Jason Yamaki

• Dsup
• Tardigrade
• DNA damage suppressor
• radiation
• protection
• IDP
• Medicinal and Pharmaceutical Chemistry

Repository record dc:identifier

https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/45

OAI identifier oai:identifier

oai:digitalcommons.chapman.edu:pharmaceutical_sciences_dissertations-1046