2. Academic Validation
  3. Systematic discovery of UFM1 receptors reveals a regulatory module in DNA repair directing non-homologous end-joining

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

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.

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