Discovery of an Endonuclease G-inhibitory Ku80-peptide protecting against leukemogenic rearrangements at the MLL breakpoint cluster.
A new Ku80-derived peptide just landed in the peptide research spotlight. Researchers at Ulm University found a 28-amino-acid sequence from the C-terminus of human Ku80—dubbed Ku3—that can block Endonuclease G (EndoG), a DNA-cleaving enzyme notorious for driving chromosomal breakage at the MLL breakpoint cluster region (MLLbcr) during chemotherapy. This region is a hot spot for rearrangements that can lead to therapy-related leukemia.
Nat Commun
by Eberle J, Salem A, Hofmann M et al.
“Discovery of an Endonuclease G-inhibitory Ku80-peptide protecting against leukemogenic rearrangements at the MLL breakpoint cluster. Eberle J(#)(1), Salem A(#)(1), Hofmann M(#)(2)(3), Reisser A(#)(2), Ruiz-Blanco YB(#)(4), Almeida-Hernandez Y(5), Gole B(1)(6), Rall-Scharpf M(1), Angulo-Capel J(2)(7), Monecke T(8), Sanchez-Garcia E(9)(10), Gebhardt JCM(11)(12), Wiesmüller L(13). Author information: (1)Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany. (2)Department of Physics, Institute of Biophysics, Ulm University, Ulm, Germany. (3)Department of Physics, Institute of Experimental Physics, Ulm University, Ulm, Germany. (4)Department of Biology, Computational Biochemistry, University of Duisburg-Essen, Essen, Germany. (5)Department of Biochemical and Chemical Engineering, Chair of Computational Bioengineering, Technical University Dortmund, Dortmund, Germany. (6)Centre for human molecular genetics and pharmacogenomics, Faculty of Medicine, University of Maribor, SI, Maribor, Slovenia. (7)Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 149-153, Barcelona, Spain. (8)Institute of Pharmaceutical Biotechnology, Ulm University, James-Franck-Ring N27, Ulm, Germany. (9)Department of Biology, Computational Biochemistry, University of Duisburg-Essen, Essen, Germany. elsa.sanchez@tu-dortmund.de. (10)Department of Biochemical and Chemical Engineering, Chair of Computational Bioengineering, Technical University Dortmund, Dortmund, Germany. elsa.sanchez@tu-dortmund.de. (11)Department of Physics, Institute of Biophysics, Ulm University, Ulm, Germany. christof.gebhardt@uni-ulm.de. (12)Department of Physics, Institute of Experimental Physics, Ulm University, Ulm, Germany. christof.gebhardt@uni-ulm.de. (13)Department of Obstetrics and Gynecology, Ulm University, Ulm, Germany. lisa.wiesmueller@uni-ulm.de. (#)Contributed equally Endonuclease G (EndoG) is an evolutionarily conserved enzyme that cleaves the Mixed Lineage Leukemia breakpoint cluster region (MLLbcr) under sublethal chemotherapeutic treatment conditions, causing leukemogenic chromosomal rearrangements. While endogenous inhibitors (EndoGI) control EndoG in lower organisms, no such EndoGI has been identified in mammalian cells. Due to the structural similarity of EndoGI from Drosophila melanogaster to the C-terminus (Ct) of human Ku80, we perform immunoprecipitation, surface plasmon resonance analysis and 3D molecular modeling, revealing binding of human EndoG to Ku80-Ct putatively between amino acid 110-184. Docking modeling predicts EndoGI-like peptides clustering around residues 686-707 of Ku80. Our experimental studies provide evidence that Ku80-Ct and 28-mer peptide Ku3 reduce MLLbcr breakage after doxorubicin treatment independently of DNA-PK activity. Proximity ligation and single molecule tracking studies show that Ku3 antagonizes Ku80-EndoG association and modulates chromatin-binding of EndoG. Such MLLbcr protection blocks EndoG´s pro-tumorigenic functions without limiting cytotoxicity, pursued for co-treatments that reduce secondary leukemia, a severe side effect of chemotherapy. © 2026. The Author(s). Conflict of interest statement: Competing interests: The authors Lisa Wiesmüller, Boris Gole, Julia Eberle (née Wille), J. Christof M. Gebhardt, Anja Reisser (née Palmer), Yasser Bruno Ruiz-Blanco, Elsa Sanchez-Garcia are the inventors of the patent with application number PCT/EP2023/051816; applicant: Ulm University, Germany; status of application: Filed international on January 25, 2023; specific aspect of manuscript covered in patent application: Identification of peptide derived from human Ku80 for use in the prevention of genomic rearrangements causing therapy-related leukemia. The remaining authors declare no competing interests.”
Here’s what matters: EndoG’s unwanted activity has been a mystery problem in mammalian cells. Lower organisms have natural inhibitors, but until now, nothing similar had shown up in humans. The team noticed the structural similarity between EndoG inhibitors in fruit flies and the human Ku80 protein, then used immunoprecipitation, surface plasmon resonance, and 3D molecular modeling to map out the interaction. They pinned down the binding site to amino acids 110-184 on Ku80, but the real action comes from a synthetic peptide mapped to residues 686-707.
Key takeaway: The Ku3 peptide shuts down EndoG’s pro-tumorigenic functions without getting in the way of chemotherapy’s main event—killing cancer cells. Their experiments showed Ku3 stopped MLLbcr breakage after doxorubicin exposure, and did it without touching DNA-PK activity. In other words, Ku3 acts specifically and doesn’t mess with the broader DNA repair machinery.
Ku3 peptide could help researchers explore ways to reduce secondary leukemia risk during cancer treatment
The approach leverages smart peptide design, not blunt force disruption of normal cellular processes
There’s a filed patent on this peptide, so expect more developments. This is a big win for anyone interested in targeted peptide-based genome protection strategies. For more on the latest in peptide research, check out our growing database.
This discovery brings a fresh angle to how researchers can use peptides to influence DNA repair—one precise interaction at a time.
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