Scholarlink

<p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月15日

查看全文
  • 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

摘要

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.