In a quiet lab at the University of Dundee, a tiny enzyme named MINDY3 is rewriting what we know about how cells protect themselves. For the first time, scientists have uncovered a direct molecular bridge between two of life’s most essential maintenance systems: protein quality control and DNA repair. Led by researchers from the MRC Protein Phosphorylation and Ubiquitylation Unit at Dundee, in collaboration with teams from ETH Zürich, the Malopolska Center of Biotechnology, and the University of Veterinary Medicine Vienna, the discovery centers on MINDY3—a deubiquitinase with a surprising secret. Its EF-hand domain, once thought to only sense calcium, actually functions as a sophisticated dual-purpose sensor, binding both ubiquitin chains and the UBL domains of RAD23A and RAD23B. These RAD23 proteins are cellular couriers, shuttling damaged proteins to the proteasome for disposal—a process now directly linked to DNA repair.

The significance lies in timing and location. When DNA is damaged, cells must rapidly stabilize repair machinery while clearing away misfolded or harmful proteins. MINDY3, guided by RAD23, arrives at the scene of DNA lesions, where it can precisely trim long polyubiquitin chains on RAD23-bound cargo. This fine-tuning may determine whether a protein is saved, redirected, or destroyed—critical decisions in maintaining genomic stability. Using crystallography, the team mapped the exact interface between MINDY3’s EF-hand and RAD23A’s UBL domain, identifying key residues that make this interaction possible. Complementary experiments—ITC measurements, pull-down assays, and live-cell imaging—confirmed that disrupting this interface impairs MINDY3’s recruitment to DNA damage sites.

What makes MINDY3 unique is its triple-binding surface within the EF-hand, allowing it to latch onto long ubiquitin chains with high specificity, a trait uncommon among deubiquitinases. This structural innovation enables MINDY3 to act not just as a passive passenger, but as an active regulator at the intersection of protein degradation and genome integrity. "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," says Professor Sebastian Glatt of Vetmeduni and the Małopolska Center of Biotechnology.

Published in EMBO Reports (2026), this work opens new avenues for understanding diseases rooted in protein misfolding and DNA instability, such as cancer and neurodegenerative disorders. By revealing how MINDY3 couples ubiquitin signaling to DNA repair through RAD23, scientists now have a fresh target for probing cellular resilience. As research shifts toward therapeutic manipulation of deubiquitinases, MINDY3 stands out—not as a loud disruptor, but as a quiet conductor, orchestrating balance in the cell’s most critical moments.