ArticleThe Journal of biological chemistry2016
An Intrinsically Disordered APLF Links Ku, DNA-PKcs, and XRCC4-DNA Ligase IV in an Extended Flexible Non-homologous End Joining Complex.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 74 citations in OpenAlex.
- End processing in NHEJ by Polymerase λ and PNKP is coordinated during short-range synapsis.Nature communications · 2026Article
- DNA-PK driven nucleosome unwrapping enables NHEJ in chromatin.Nature communications · 2026Article
- Nonhomologous end joining-the importance of end tethering and beyond.Genes & development · 2026Review
- Decoding replication stress responses through post-translational modifications.Nature chemical biology · 2025Review
- Review
- Mechanism of cytarabine-induced neurotoxicity.Nature · 2025Article
- Multivalent interactions of the disordered regions of XLF and XRCC4 foster robust cellular NHEJ and drive the formation of ligation-boosting condensates in vitro.Nature structural & molecular biology · 2024Article
- APLF facilitates interstrand DNA crosslink repair and replication fork protection to confer cisplatin resistance.Nucleic acids research · 2024Article
- Biological functions and clinic significance of SAF‑A (Review).Biomedical reports · 2024Review
- Mammalian DNA ligases; roles in maintaining genome integrity.Journal of molecular biology · 2024Review
- Structure and mechanism in non-homologous end joining.DNA repair · 2023Article
- Structure and function of the apical PIKKs in double-strand break repair.Current opinion in structural biology · 2023Review
- Cryo-EM visualization of DNA-PKcs structural intermediates in NHEJ.Science advances · 2023Article
- Chaperoning of the histone octamer by the acidic domain of DNA repair factor APLF.Science advances · 2022Article
- Species variations in XRCC1 recruitment strategies for FHA domain-containing proteins.DNA repair · 2022Article
- Purification and Characterization of Human DNA Ligase IIIα Complexes After Expression in Insect Cells.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Universally Accessible Structural Data on Macromolecular Conformation, Assembly, and Dynamics by Small Angle X-Ray Scattering for DNA Repair Insights.Methods in molecular biology (Clifton, N.J.) · 2022Article
- Chaperoning histones at the DNA repair dance.DNA repair · 2021Review
- DNA End Joining: G0-ing to the Core.Biomolecules · 2021Review
- Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma.Cancer research · 2021Article
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
Abstract
DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) in human cells is initiated by Ku heterodimer binding to a DSB, followed by recruitment of core NHEJ factors including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), XRCC4-like factor (XLF), and XRCC4 (X4)-DNA ligase IV (L4). Ku also interacts with accessory factors such as aprataxin and polynucleotide kinase/phosphatase-like factor (APLF). Yet, how these factors interact to tether, process, and ligate DSB ends while allowing regulation and chromatin interactions remains enigmatic. Here, small angle X-ray scattering (SAXS) and mutational analyses show APLF is largely an intrinsically disordered protein that binds Ku, Ku/DNA-PKcs (DNA-PK), and X4L4 within an extended flexible NHEJ core complex. X4L4 assembles with Ku heterodimers linked to DNA-PKcs via flexible Ku80 C-terminal regions (Ku80CTR) in a complex stabilized through APLF interactions with Ku, DNA-PK, and X4L4. Collective results unveil the solution architecture of the six-protein complex and suggest cooperative assembly of an extended flexible NHEJ core complex that supports APLF accessibility while possibly providing flexible attachment of the core complex to chromatin. The resulting dynamic tethering furthermore, provides geometric access of L4 catalytic domains to the DNA ends during ligation and of DNA-PKcs for targeted phosphorylation of other NHEJ proteins as well as trans-phosphorylation of DNA-PKcs on the opposing DSB without disrupting the core ligation complex. Overall the results shed light on evolutionary conservation of Ku, X4, and L4 activities, while explaining the observation that Ku80CTR and DNA-PKcs only occur in a subset of higher eukaryotes.
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