Programmable DNA protonuclei reveal environmental context on protein phase separation
Abstract
Understanding protein phase separation in cellular environments remains a major challenge, as ex vivo assays often fail to capture the influence of environmental context – such as crowding, multimodal interactions, and the dynamic properties of the cytosol or nucleus. Here, we introduce programmable DNA-based protonuclei (PN) as nucleus-inspired compartments to probe phase separation of the neurodegeneration-linked protein FUS. We show that FUS partitioning and condensate formation are highly sensitive to nucleic acid sequence, spatial confinement, and viscoelastic properties of the PN core. Notably, classical test-tube affinity assays fail to predict protein behavior within the crowded and multivalent PN environment. By tuning DNA crosslinking, we modulate condensate dynamics and suppress liquid-to-solid transitions of FUS – a hallmark of disease. These findings demonstrate that multivalent, confined environments fundamentally reshape protein-nucleic acid interactions and phase behavior. The PN platform complements test-tube assays and complex cellular settings and enables to dissect nuclear condensates under controllable conditions.
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BibTeX
@article{fritzen2026programmable,
title = {{Programmable DNA protonuclei reveal environmental context on protein phase separation}},
author = {Johann Fritzen and Avik Samanta and Nele S. Kuhr and Antonia Preuß and Erin L. Sternburg and Lukas S. Stelzl and Jasper J. Michels and Dorothee Dormann and Andreas Walther},
journal = {Nature Communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-78144-1},
url = {https://www.nature.com/articles/s41467-026-78144-1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Programmable DNA protonuclei reveal environmental context on protein phase separation
AU - Johann Fritzen
AU - Avik Samanta
AU - Nele S. Kuhr
AU - Antonia Preuß
AU - Erin L. Sternburg
AU - Lukas S. Stelzl
AU - Jasper J. Michels
AU - Dorothee Dormann
AU - Andreas Walther
PY - 2026
DA - 2026/09/30
JO - Nature Communications
DO - 10.1038/s41467-026-78144-1
UR - https://www.nature.com/articles/s41467-026-78144-1
AB - Understanding protein phase separation in cellular environments remains a major challenge, as ex vivo assays often fail to capture the influence of environmental context – such as crowding, multimodal interactions, and the dynamic properties of the cytosol or nucleus. Here, we introduce programmable DNA-based protonuclei (PN) as nucleus-inspired compartments to probe phase separation of the neurodegeneration-linked protein FUS. We show that FUS partitioning and condensate formation are highly sensitive to nucleic acid sequence, spatial confinement, and viscoelastic properties of the PN core. Notably, classical test-tube affinity assays fail to predict protein behavior within the crowded and multivalent PN environment. By tuning DNA crosslinking, we modulate condensate dynamics and suppress liquid-to-solid transitions of FUS – a hallmark of disease. These findings demonstrate that multivalent, confined environments fundamentally reshape protein-nucleic acid interactions and phase behavior. The PN platform complements test-tube assays and complex cellular settings and enables to dissect nuclear condensates under controllable conditions.
SN - 2041-1723
ER -