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| Title | Dynamic assemblies and coordinated reactions of non-homologous end joining. |
|---|---|
| Journal, issue, pages | Nature, Vol. 643, Issue 8072, Page 847-854, Year 2025 |
| Publish date | Jun 11, 2025 |
 Authors | Lan Liu / Jun Li / Metztli Cisneros-Aguirre / Arianna Merkell / Jeremy M Stark / Martin Gellert / Wei Yang /  |
| PubMed Abstract | Non-homologous end joining (NHEJ) is the main repair pathway of double-strand DNA breaks in higher eukaryotes. Here we report reconstitution of the final steps of NHEJ and structures of DNA ...Non-homologous end joining (NHEJ) is the main repair pathway of double-strand DNA breaks in higher eukaryotes. Here we report reconstitution of the final steps of NHEJ and structures of DNA polymerase μ and ligase IV (LIG4) engaged in gap filling and end joining. These reactions take place in a flexible ω-shaped framework composed of XRCC4 and XLF. Two broken DNA ends, each encircled by Ku70-Ku80 internally, are docked onto the ω frame, mediated by LIG4. DNA polymerase and ligase attached to each ω arm repair only one broken strand of a defined polarity; the final steps of NHEJ requires coordination and toggling of a pair of such enzymes. The facilitators XLF and PAXX additively stimulate NHEJ reactions. As DNA-end sensor and protector, LIG4 replaces DNA-PKcs for end joining and bridges the two DNA ends for polymerase to fill remaining gaps. These assemblies present new targets for NHEJ inhibition to enhance efficacy of radiotherapy and accuracy of gene editing. |
 External links | Nature / PubMed:40500445 |
| Methods | EM (single particle) |
| Resolution | 2.7 - 7.4 Å |
| Structure data | EMDB-45807, PDB-9cq3: EMDB-45809, PDB-9cq6: EMDB-45813, PDB-9cqc:  EMDB-45838: Consensus map of the gap-filling complex with Pol mu engaged in the NHEJ pathway  EMDB-45839: Focused map of polymerase mu and ligase IV DBD in a gap-filling complex in the NHEJ pathway  EMDB-45840: Focused map of Ku70/80 complex on the active side of a gap-filling complex with Pol mu engaged in the NHEJ pathway  EMDB-45841: Focused map of XRCC4/Ligase IV on the active side of a gap-filling complex with Pol mu engaged in the NHEJ pathway  EMDB-45842: Focused map of the Ku70/80 complex on the supportive side of a gap-filling complex with Pol mu engaged in the NHEJ pathway  EMDB-45843: Focused map of XRCC4/Ligase IV complex on the supportive side of a gap-filling complex with Pol mu engaged in the NHEJ pathway  EMDB-45844: Focused map of XLF in a gap-filling complex with Pol mu engaged in the NHEJ pathway  EMDB-45845: Focused map of Ligase IV NTD and DBD in a gap-filling complex with Pol mu engaged in the NHEJ pathway  EMDB-45846: Focused map of PAXX/XLF in a gap-filling complex with Pol mu engaged in the NHEJ pathway  EMDB-45847: Consensus map of ligation complex in the NHEJ pathway  EMDB-45849: Focused map of Ku70/80 on the active side of the ligation complex in the NHEJ pathway  EMDB-45850: Focused map of XRCC4/Ligase IV on the active side of ligation complex in the NHEJ pathway  EMDB-45851: Focused map of Ku70/80 on the supportive side of ligation complex in the NHEJ pathway  EMDB-45852: Focused map of XRCC4/Ligase IV on the supportive side of the ligation complex in the NHEJ pathway  EMDB-45853: Focused map of XLF in ligation complex in the NHEJ pathway  EMDB-45855: The consensus map of ligation complex II in the NHEJ pathway  EMDB-45857: Focused map of ligase IV catalytic domain in ligation complex II in the NHEJ complex  EMDB-45858: Focused map of Ku70/80 complex on the active side of the ligation complex II in the NHEJ pathway  EMDB-45859: Focused map of XRCC4/Ligase IV complex on the active site of the ligation complex like in the NHEJ pathway  EMDB-45860: Focused map of Ku70/80 complex on the supportive side of the ligation complex like in the NHEJ pathway  EMDB-45861: Focused map of XRCC4/Ligase IV on the supportive side of ligation complex like in the NHEJ pathway  EMDB-45862: Focused map of XLF in ligation complex like in the NHEJ pathway EMDB-49108, PDB-9n81: EMDB-49109, PDB-9n82: EMDB-49110, PDB-9n83:  EMDB-49112: A Ligation complex in NHEJ pathway (AMP-Lys and AMP-DNA mix states)  EMDB-49115: Focused map of Pol mu part in a gap-filling complex in the NHEJ pathway  EMDB-49132: Focused map of Ku70/80 complex on the active side of a gap-filling complex in NHEJ complex  EMDB-49133: Focused map of Ku70/80 complex on the supportive side of a gap-filling complex in NHEJ pathway  EMDB-49134: Focused map of XRCC4-Ligase IV complex on the active side of a gap-filling complex in NHEJ pathway  EMDB-49135: Focused map of XRCC4-Ligase IV complex on the supportive side of a gap-filling complex in NHEJ pathway  EMDB-49136: Focused map of XLF in a gap-filling complex in NHEJ pathway  EMDB-49137: Focused map of Ligase IV N-terminal domain (NTD) in a gap-filling complex in NHEJ pathway  EMDB-49138: Focused map of Ku70/80 complex on the active side of the ligation complexes in the NHEJ pathway  EMDB-49139: Focused map of Ku70/80 complex on the supportive side of the ligation complexes in the NHEJ pathway  EMDB-49140: Focused map of XRCC4-Ligase IV complex on the active side of the ligation complexes in the NHEJ pathway  EMDB-49141: Focused map of XRCC4-Ligase IV complex on the supportive side of the ligation complexes in the NHEJ pathway  EMDB-49142: Focused map of XLF in the ligation complexes in the NHEJ pathway  EMDB-49143: Focused map of Ligase IV catalytic domains of the ligation complex (AMP-Lys) in the NHEJ pathway  EMDB-49144: Focused map of Ligase IV catalytic domains of the ligation complex (AMP-DNA) in the NHEJ pathway  EMDB-49244: a ligation complex in NHEJ pathway  EMDB-49245: a ligation complex (AMP-Lys) in the NHEJ pathway  EMDB-49246: a gap-filling complex with pol mu engaged in the NHEJ pathway  EMDB-49247: A Ligation complex in NHEJ pathway (AMP-Lys and AMP-DNA mix states) |
| Chemicals |  ChemComp-MG:  ChemComp-DZ4:  ChemComp-AMP: |
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 Keywords | LIGASE/TRANSFERASE/DNA / NHEJ / DNA gap / fill-in synthesis / ligation / XLF / PAXX / Polymerase mu / DNA repair / Ligase IV / LIGASE-TRANSFERASE-DNA complex / Pol mu |
homo sapiens (human)