Researchers from the MRC Protein Phosphorylation and Ubiquitylation Unit at the University of Dundee, together with collaborators from ETH Zürich, the Malopolska Center of Biotechnology and the University of Veterinary Medicine Vienna, report a new link between protein quality control and DNA damage responses. The work centers on MINDY3, a deubiquitinase enzyme, and reveals that it carries a distinctive EF-hand region that acts as a novel ubiquitin-binding domain.
This EF-hand contains three binding surfaces that let MINDY3 recognize and cleave long polyubiquitin chains more efficiently, a key step in controlling protein fate inside cells. Crucially, the EF-hand of MINDY3 binds not only to ubiquitin chains but also to the UBL (ubiquitin-like) domains of RAD23A and RAD23B, proteins that help shuttle ubiquitylated cargo to the proteasome for degradation. The paper is published in the journal EMBO Reports.
This discovery links MINDY3 to the RAD23–proteasome axis, guiding MINDY3 to sites where DNA damage has occurred and suggesting a coordinated role in protein quality control during DNA repair processes. Sebastian Glatt, professor of systems genetics at Vetmeduni and group leader at the Ma?opolska Center of Biotechnology (MCB) at Jagiellonian University, states, “The key takeaway is that cells have intricate “quality-control” systems to manage damaged proteins and repair DNA—our work uncovers a new piece of that complex molecular puzzle.”
Structure meets cell biology—MINDY3 at the damage site
The research team solved the crystal structure of the MINDY3 EF-hand in complex with the RAD23A UBL domain, revealing the molecular details of this interaction and identifying specific interface residues essential for binding. These structural insights explain how MINDY3 recognizes RAD23A (and RAD23B) while remaining distinct from other ubiquitin interactions.
Guided by RAD23: MINDY3 at the site of DNA repair
In cellular experiments, RAD23A/B influence where MINDY3 localizes when DNA damage is present, supporting a model in which MINDY3 can deubiquitylate RAD23-bound substrates at damage sites, potentially shaping the fate of those proteins during repair.
The study uses a multidisciplinary approach—biochemistry, structural biology and cell biology—to build a comprehensive picture. Techniques include crystallography to map the binding interface, isothermal titration calorimetry (ITC) to measure interactions, pull-downs to confirm partnerships and live-cell imaging to track MINDY3’s recruitment to DNA lesions. Together, these methods support a model in which the MINDY3 EF-hand acts as a dedicated ubiquitin-binding module that recognizes long ubiquitin chains and couples this signaling to DNA repair pathways via RAD23A/B.
Publication details
Lee A Armstrong et al, The EF-hand domain of MINDY3 is a ubiquitin and RAD23 UBL-binding domain, EMBO Reports (2026). DOI: 10.1038/s44319-026-00825-1
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University of Veterinary Medicine—Vienna
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