Authors
Zijuan Wang, Benjamin M Foster, Isabelle C da Costa, Yue Wu, Deepak Behera, Francesca Conte, Eleanor W Trotter, Felicia Wednesday Lopezcolorado, Maria Jose Cabello-Lobato, Shweta Choudhary, Reuven Wiener, Petra Beli, Duncan L Smith, William H Banks, Steven Bagley, Shane McKee, Meenakshi Minnis, Stefan Meyer, Amanda K Chaplin, Wolfgang Dörner, Henning D Mootz, Iain M Hagan, Yaron Galanty, Jeremy M Stark, Igor Larrosa, Matthew J Cliff, Christine K Schmidt
Published in
Nature communications. Jun 15, 2026. Epub Jun 15, 2026.
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.
PMID:
42297806
Bibliographic data and abstract were imported from PubMed on 16 Jun 2026.
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