Systematic discovery of UFM1 receptors reveals a regulatory module in DNA repair directing non-homologous end-joining

  • Nat Commun. 2026 Jun 15. doi: 10.1038/s41467-026-73882-8.
Zijuan Wang  #  1 ,  Benjamin M Foster  #  1 ,  Isabelle C da Costa  #  1 ,  Yue Wu  1 ,  Deepak Behera  1  2 ,  Francesca Conte  3 ,  Eleanor W Trotter  4 ,  Felicia Wednesday Lopezcolorado  5 ,  Maria Jose Cabello-Lobato  1 ,  Shweta Choudhary  2 ,  Reuven Wiener  6 ,  Petra Beli  3  7 ,  Duncan L Smith  8 ,  William H Banks  9 ,  Steven Bagley  9 ,  Shane McKee  10 ,  Meenakshi Minnis  11  12 ,  Stefan Meyer  1  13  14 ,  Amanda K Chaplin  15 ,  Wolfgang Dörner  16 ,  Henning D Mootz  16 ,  Iain M Hagan  4 ,  Yaron Galanty  17  18 ,  Jeremy M Stark  5 ,  Igor Larrosa  2 ,  Matthew J Cliff  19  20 ,  Christine K Schmidt  21
Affiliations
  • 1. Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • 2. Department of Chemistry, School of Natural Sciences, University of Manchester, Manchester, UK.
  • 3. Institute of Molecular Biology (IMB), Mainz, Germany.
  • 4. Cell Division Group, CRUK Manchester Institute, The University of Manchester, Manchester, UK.
  • 5. Department of Cancer Genetics and Epigenetics, Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, 1500 E Duarte Rd, Duarte, CA, USA.
  • 6. Department of Biochemistry and Molecular Biology, The Institute for Medical Research, Israel-Canada Hebrew University-Hadassah Medical School, Jerusalem, Israel.
  • 7. Institute of Developmental Biology and Neurobiology (IDN), Johannes Gutenberg-Universität, Mainz, Germany.
  • 8. Mass spectrometry, CRUK Manchester Institute, The University of Manchester, Manchester, UK.
  • 9. Microscopy, CRUK Manchester Institute, The University of Manchester, Manchester, UK.
  • 10. Department of Genetic Medicine, Belfast City Hospital, Belfast, UK.
  • 11. Manchester Academic Health Science Centre, Manchester, UK.
  • 12. Department of Genetic Medicine, St Mary's Hospital, Central Manchester NHS Foundation Trust, Manchester, UK.
  • 13. Department of Paediatric Haematology and Oncology, Royal Manchester Children's Hospital, Manchester, UK.
  • 14. Young Oncology Unit, The Christie NHS Foundation Trust, Manchester, UK.
  • 15. Leicester Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology, University of Leicester, Leicester, UK.
  • 16. Institute of Biochemistry, University of Münster, Münster, Germany.
  • 17. The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, UK.
  • 18. CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
  • 19. Department of Chemistry, School of Natural Sciences, University of Manchester, Manchester, UK. [email protected].
  • 20. Manchester Institute of Biotechnology (MIB), University of Manchester, Manchester, UK. [email protected].
  • 21. Manchester Cancer Research Centre, Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. [email protected].
  • # Contributed equally.
PMID: 42297806 DOI: 10.1038/s41467-026-73882-8
Abstract

Posttranslational modifications with ubiquitin-like modifiers (UBLs) are critical for genome maintenance, yet many remain mechanistically uncharacterised. Here, we identify UFM1 as a key regulator of non-homologous end-joining (NHEJ), a major DNA double-strand break repair pathway. Using a structure-guided chemical biology approach, we develop a photo-crosslinkable UFM1 probe and, in combination with NMR, map non-canonical UFM1-binding interfaces in core NHEJ factors, including the disordered XRCC4 tail. Mechanistically, proximity-dependent proteomics and functional assays identify Ku70 as a crucial UFMylation substrate and reveal a UFM1-dependent axis in which XRCC4 engages UFMylated Ku70 to stabilise NHEJ complex assembly on chromatin. Disruption of this molecular mechanism via UFSP2 depletion or a hypomorphic UBA5 variant in patient-derived cells impairs NHEJ function, linking UFMylation defects to compromised genome integrity processes. Our findings define a complete UFM1 signalling module in DNA repair and establish a generalisable framework for dissecting low-affinity UBL networks with broad functional and disease relevance.

Products