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| Title | Cryo-EM structures of NHEJ assemblies with nucleosomes. |
|---|---|
| Journal, issue, pages | Nat Commun, Year 2025 |
| Publish date | Dec 24, 2025 |
Authors | 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 / ![]() |
| PubMed Abstract | 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 ...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. |
External links | Nat Commun / PubMed:41444611 |
| Methods | EM (single particle) |
| Resolution | 2.94 - 5.0 Å |
| Structure data | EMDB-52860, PDB-9igw: EMDB-52861, PDB-9igx: EMDB-52879, PDB-9q80: EMDB-52912, PDB-9q8x: EMDB-52958, PDB-9q9f: EMDB-53025, PDB-9qcr: EMDB-53026, PDB-9qcs: EMDB-53237, PDB-9qms: |
| Source |
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Keywords | DNA BINDING PROTEIN / DNA-binding protein / NHEJ / Ku70/80 / nucleosome |
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homo sapiens (human)
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