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- PDB-9iol: Cryo-EM structure of the complex of DNA, Ku70/80, and laXLF. -

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Basic information

Entry
Database: PDB / ID: 9iol
TitleCryo-EM structure of the complex of DNA, Ku70/80, and laXLF.
Components
  • (X-ray repair cross-complementing protein ...) x 2
  • DNA (5'-D(P*AP*GP*GP*TP*CP*GP*AP*CP*GP*AP*AP*TP*CP*GP*GP*CP*AP*GP*CP*G)-3')
  • DNA (5'-D(P*CP*GP*CP*TP*GP*CP*CP*GP*AP*TP*TP*CP*GP*TP*CP*GP*AP*CP*CP*T)-3')
  • Peptide from Non-homologous end-joining factor 1
KeywordsDNA BINDING PROTEIN/DNA / DNA repair / NHEJ / Complex / Lactylation / DNA BINDING PROTEIN / DNA BINDING PROTEIN-DNA complex
Function / homology
Function and homology information


positive regulation of ligase activity / DNA ligase IV complex / Ku70:Ku80 complex / negative regulation of t-circle formation / DNA end binding / small-subunit processome assembly / positive regulation of lymphocyte differentiation / DNA-dependent protein kinase complex / DNA-dependent protein kinase-DNA ligase 4 complex / immunoglobulin V(D)J recombination ...positive regulation of ligase activity / DNA ligase IV complex / Ku70:Ku80 complex / negative regulation of t-circle formation / DNA end binding / small-subunit processome assembly / positive regulation of lymphocyte differentiation / DNA-dependent protein kinase complex / DNA-dependent protein kinase-DNA ligase 4 complex / immunoglobulin V(D)J recombination / nonhomologous end joining complex / regulation of smooth muscle cell proliferation / cellular response to X-ray / nuclear telomere cap complex / double-strand break repair via classical nonhomologous end joining / Cytosolic sensors of pathogen-associated DNA / IRF3-mediated induction of type I IFN / positive regulation of neurogenesis / recombinational repair / regulation of telomere maintenance / protein localization to chromosome, telomeric region / U3 snoRNA binding / cellular hyperosmotic salinity response / response to ionizing radiation / 2-LTR circle formation / hematopoietic stem cell proliferation / telomeric DNA binding / positive regulation of protein kinase activity / Lyases; Carbon-oxygen lyases; Other carbon-oxygen lyases / site of DNA damage / T cell differentiation / 5'-deoxyribose-5-phosphate lyase activity / hematopoietic stem cell differentiation / ATP-dependent activity, acting on DNA / telomere maintenance via telomerase / DNA polymerase binding / neurogenesis / activation of innate immune response / telomere maintenance / DNA helicase activity / cyclin binding / cellular response to leukemia inhibitory factor / B cell differentiation / central nervous system development / small-subunit processome / Nonhomologous End-Joining (NHEJ) / enzyme activator activity / cellular response to gamma radiation / protein-DNA complex / double-strand break repair via nonhomologous end joining / Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement / fibrillar center / double-strand break repair / site of double-strand break / double-stranded DNA binding / scaffold protein binding / secretory granule lumen / DNA recombination / transcription regulator complex / ficolin-1-rich granule lumen / damaged DNA binding / chromosome, telomeric region / transcription cis-regulatory region binding / ribonucleoprotein complex / innate immune response / negative regulation of DNA-templated transcription / DNA damage response / ubiquitin protein ligase binding / Neutrophil degranulation / positive regulation of DNA-templated transcription / protein-containing complex binding / nucleolus / positive regulation of transcription by RNA polymerase II / protein-containing complex / ATP hydrolysis activity / DNA binding / RNA binding / extracellular region / nucleoplasm / ATP binding / nucleus / membrane / plasma membrane / cytosol
Similarity search - Function
XLF, N-terminal / : / : / XLF N-terminal domain / XLF protein coiled-coil region / XRCC4-like, N-terminal domain superfamily / Ku70, bridge and pillars domain superfamily / : / Ku70 / Ku, C-terminal ...XLF, N-terminal / : / : / XLF N-terminal domain / XLF protein coiled-coil region / XRCC4-like, N-terminal domain superfamily / Ku70, bridge and pillars domain superfamily / : / Ku70 / Ku, C-terminal / Ku, C-terminal domain superfamily / Ku C terminal domain like / Ku80 / Ku70/Ku80 C-terminal arm / Ku70/Ku80 C-terminal arm / Ku70/Ku80, N-terminal alpha/beta / Ku70/Ku80 N-terminal alpha/beta domain / Ku70/Ku80 beta-barrel domain / Ku70 and Ku80 are 70kDa and 80kDa subunits of the Lupus Ku autoantigen / Ku70/Ku80 beta-barrel domain / SPOC-like, C-terminal domain superfamily / SAP domain superfamily / SAP motif profile. / SAP domain / Putative DNA-binding (bihelical) motif predicted to be involved in chromosomal organisation / SAP domain / von Willebrand factor (vWF) type A domain / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily
Similarity search - Domain/homology
(2S)-2-HYDROXYPROPANOIC ACID / INOSITOL HEXAKISPHOSPHATE / DNA / DNA (> 10) / X-ray repair cross-complementing protein 6 / X-ray repair cross-complementing protein 5 / Non-homologous end-joining factor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsLiang, S.
Funding support Hong Kong, 1items
OrganizationGrant numberCountry
Other private Hong Kong
CitationJournal: Mol Cell / Year: 2025
Title: Lactylation of XLF promotes non-homologous end-joining repair and chemoresistance in cancer.
Authors: Mingpeng Jin / Bingsong Huang / Xiaoning Yang / Shuyang Wang / Jinhuan Wu / Yiming He / Xin Ding / Xuanhe Wang / Zhe Wang / Jie Yang / Rui Li / Xuan Zhou / Qianwen Wang / Yunhui Li / Lei Li ...Authors: Mingpeng Jin / Bingsong Huang / Xiaoning Yang / Shuyang Wang / Jinhuan Wu / Yiming He / Xin Ding / Xuanhe Wang / Zhe Wang / Jie Yang / Rui Li / Xuan Zhou / Qianwen Wang / Yunhui Li / Lei Li / Wen Zheng / Zhikai Zeng / Chenxi Zhao / Jiaqi Liu / Qian Zhu / Zhihua Kang / Ke Li / Shikang Liang / Yuping Chen / Jian Yuan /
Abstract: Metabolic reprogramming and DNA damage repair are essential in tumorigenesis and chemoresistance, yet their link remains elusive. Here, we show that LDHA deficiency impairs NHEJ and class switch ...Metabolic reprogramming and DNA damage repair are essential in tumorigenesis and chemoresistance, yet their link remains elusive. Here, we show that LDHA deficiency impairs NHEJ and class switch recombination. Additionally, glycolysis-derived lactate promotes XLF lactylation at K288 within its Ku-binding motif (X-KBM) to regulate NHEJ. Mechanistically, DNA damage triggers ATM-mediated GCN5 phosphorylation to increase GCN5-XLF interaction and XLF lactylation, enhancing XLF-Ku80 binding, XLF recruitment to DSBs, and NHEJ efficiency. Cryo-EM structural analysis demonstrates that lactylated X-KBM (laX-KBM) forms a more extensive interface with Ku70/80, inducing conformational changes in the Ku80 vWA domain. XLF lactylation deficiency impairs NHEJ and sensitizes cancer cells to chemotherapy. A specific XLF K288 lactylation peptide inhibitor plus 5-fluorouracil synergistically kills colorectal cancer cells in PDX models with XLF hyperlactylation. These findings highlight that the GCN5-XLF lactylation axis is a critical NHEJ regulator and that targeting XLF lactylation can improve chemotherapy efficiency.
History
DepositionJul 9, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 9, 2025Provider: repository / Type: Initial release
Revision 1.0Jul 9, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 9, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: X-ray repair cross-complementing protein 5
B: X-ray repair cross-complementing protein 6
C: DNA (5'-D(P*CP*GP*CP*TP*GP*CP*CP*GP*AP*TP*TP*CP*GP*TP*CP*GP*AP*CP*CP*T)-3')
D: DNA (5'-D(P*AP*GP*GP*TP*CP*GP*AP*CP*GP*AP*AP*TP*CP*GP*GP*CP*AP*GP*CP*G)-3')
M: Peptide from Non-homologous end-joining factor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,1717
Polymers168,4205
Non-polymers7502
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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X-ray repair cross-complementing protein ... , 2 types, 2 molecules AB

#1: Protein X-ray repair cross-complementing protein 5 / 86 kDa subunit of Ku antigen / ATP-dependent DNA helicase 2 subunit 2 / ATP-dependent DNA helicase ...86 kDa subunit of Ku antigen / ATP-dependent DNA helicase 2 subunit 2 / ATP-dependent DNA helicase II 80 kDa subunit / CTC box-binding factor 85 kDa subunit / CTC85 / CTCBF / DNA repair protein XRCC5 / Ku80 / Ku86 / Lupus Ku autoantigen protein p86 / Nuclear factor IV / Thyroid-lupus autoantigen / TLAA / X-ray repair complementing defective repair in Chinese hamster cells 5 (double-strand-break rejoining) / Ku80


Mass: 82812.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: XRCC5, G22P2 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P13010, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement
#2: Protein X-ray repair cross-complementing protein 6 / 5'-deoxyribose-5-phosphate lyase Ku70 / 5'-dRP lyase Ku70 / 70 kDa subunit of Ku antigen / ATP- ...5'-deoxyribose-5-phosphate lyase Ku70 / 5'-dRP lyase Ku70 / 70 kDa subunit of Ku antigen / ATP-dependent DNA helicase 2 subunit 1 / ATP-dependent DNA helicase II 70 kDa subunit / CTC box-binding factor 75 kDa subunit / CTC75 / CTCBF / DNA repair protein XRCC6 / Lupus Ku autoantigen protein p70 / Ku70 / Thyroid-lupus autoantigen / TLAA / X-ray repair complementing defective repair in Chinese hamster cells 6


Mass: 69945.039 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: XRCC6, G22P1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P12956, Hydrolases; Acting on acid anhydrides; Acting on acid anhydrides to facilitate cellular and subcellular movement, Lyases; Carbon-oxygen lyases; Other carbon-oxygen lyases

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DNA chain , 2 types, 2 molecules CD

#3: DNA chain DNA (5'-D(P*CP*GP*CP*TP*GP*CP*CP*GP*AP*TP*TP*CP*GP*TP*CP*GP*AP*CP*CP*T)-3')


Mass: 6969.472 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#4: DNA chain DNA (5'-D(P*AP*GP*GP*TP*CP*GP*AP*CP*GP*AP*AP*TP*CP*GP*GP*CP*AP*GP*CP*G)-3')


Mass: 7156.611 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)

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Protein/peptide , 1 types, 1 molecules M

#5: Protein/peptide Peptide from Non-homologous end-joining factor 1 / laXLF


Mass: 1536.907 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q9H9Q4

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Non-polymers , 2 types, 2 molecules

#6: Chemical ChemComp-IHP / INOSITOL HEXAKISPHOSPHATE / MYO-INOSITOL HEXAKISPHOSPHATE / INOSITOL 1,2,3,4,5,6-HEXAKISPHOSPHATE


Mass: 660.035 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H18O24P6 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-2OP / (2S)-2-HYDROXYPROPANOIC ACID


Mass: 90.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H6O3 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: The complex of DNA, Ku70/80, and laXLF / Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.168 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.6
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM softwareName: cryoSPARC / Category: CTF correction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 298238 / Symmetry type: POINT

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