Scholarlink

<p>DNA double-strand breaks (DSBs) are highly deleterious lesions that can trigger cell death or carcinogenesis if unrepaired or misrepaired. In mammals, most DSBs are repaired by non-homologous end joining (NHEJ), which begins when Ku70/80 binds DNA ends and recruits DNA-PKcs to form the DNA-PK holoenzyme. Although recent cryo-EM studies have resolved several NHEJ assemblies, how these factors access DSBs within nucleosomes remains unclear. Here, we present cryo-EM structures of human Ku70/80 and DNA-PK bound to nucleosomes. Ku70/80 binds the DNA end and bends it away from the nucleosome core, while the Ku70 C-terminal SAP domain makes an additional, specific DNA contact. Our DNA-PK–nucleosome structure further reveals the opening of the Ku80 vWA domain, and we show that non-hydrolysable ATP promotes synapsis by stabilising the Ku80-mediated DNA-PK dimer. These structures reveal a model for DSB recognition on nucleosomal DNA and provide insights relevant to targeting NHEJ in cancer therapy.</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

Cryo-EM structures of NHEJ assemblies with nucleosomes

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月24日

查看全文
  • Chloe Hall,
  • Philippe Frit,
  • Antonia Kefala-Stavridi,
  • Amandine Pelletier,
  • Steven W. Hardwick,
  • Himani Amin,
  • Matthew K. Bilyard,
  • Taiana Maia De Oliviera,
  • Ammarah Tariq,
  • Sayma Zahid,
  • Dimitri Y. Chirgadze,
  • Shankar Balasubramanian,
  • Katheryn Meek,
  • Virginie Ropars,
  • Jean-Baptiste Charbonnier,
  • Mauro Modesti,
  • Patrick Calsou,
  • Sébastien Britton,
  • Tom L. Blundell,
  • Thomas Schalch,
  • Amanda K. Chaplin

摘要

DNA double-strand breaks (DSBs) are highly deleterious lesions that can trigger cell death or carcinogenesis if unrepaired or misrepaired. In mammals, most DSBs are repaired by non-homologous end joining (NHEJ), which begins when Ku70/80 binds DNA ends and recruits DNA-PKcs to form the DNA-PK holoenzyme. Although recent cryo-EM studies have resolved several NHEJ assemblies, how these factors access DSBs within nucleosomes remains unclear. Here, we present cryo-EM structures of human Ku70/80 and DNA-PK bound to nucleosomes. Ku70/80 binds the DNA end and bends it away from the nucleosome core, while the Ku70 C-terminal SAP domain makes an additional, specific DNA contact. Our DNA-PK–nucleosome structure further reveals the opening of the Ku80 vWA domain, and we show that non-hydrolysable ATP promotes synapsis by stabilising the Ku80-mediated DNA-PK dimer. These structures reveal a model for DSB recognition on nucleosomal DNA and provide insights relevant to targeting NHEJ in cancer therapy.