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XLF and APLF bind Ku80 at two remote sites to ensure DNA repair by non-homologous end joining.

Nemoz C, Ropars V, Frit P, Gontier A, Drevet P, Yu J, Guerois R, Pitois A, Comte A, Delteil C, Barboule N, Legrand P, Baconnais S, Yin Y, Tadi S, Barbet-Massin E, Berger I, Le Cam E, Modesti M, Rothenberg E, Calsou P, Charbonnier JB
Nat Struct Mol Biol 25 971-980 (2018)
Related entries: 6erf, 6erg

Cited: 45 times
EuropePMC logo PMID: 30291363

Abstract

The Ku70-Ku80 (Ku) heterodimer binds rapidly and tightly to the ends of DNA double-strand breaks and recruits factors of the non-homologous end-joining (NHEJ) repair pathway through molecular interactions that remain unclear. We have determined crystal structures of the Ku-binding motifs (KBM) of the NHEJ proteins APLF (A-KBM) and XLF (X-KBM) bound to a Ku-DNA complex. The two KBM motifs bind remote sites of the Ku80 α/β domain. The X-KBM occupies an internal pocket formed by an unprecedented large outward rotation of the Ku80 α/β domain. We observe independent recruitment of the APLF-interacting protein XRCC4 and of XLF to laser-irradiated sites via binding of A- and X-KBMs, respectively, to Ku80. Finally, we show that mutation of the X-KBM and A-KBM binding sites in Ku80 compromises both the efficiency and accuracy of end joining and cellular radiosensitivity. A- and X-KBMs may represent two initial anchor points to build the intricate interaction network required for NHEJ.

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Reviews citing this publication (13)

  1. The molecular basis and disease relevance of non-homologous DNA end joining. Zhao B, Rothenberg E, Ramsden DA, Lieber MR. Nat Rev Mol Cell Biol 21 765-781 (2020)
  2. Repair of DNA Double-Strand Breaks by the Nonhomologous End Joining Pathway. Stinson BM, Loparo JJ. Annu Rev Biochem 90 137-164 (2021)
  3. The Multifaceted Roles of Ku70/80. Zahid S, Seif El Dahan M, Iehl F, Fernandez-Varela P, Le Du MH, Ropars V, Charbonnier JB. Int J Mol Sci 22 4134 (2021)
  4. X-ray scattering reveals disordered linkers and dynamic interfaces in complexes and mechanisms for DNA double-strand break repair impacting cell and cancer biology. Hammel M, Tainer JA. Protein Sci 30 1735-1756 (2021)
  5. Preserving genome integrity in human cells via DNA double-strand break repair. Jensen RB, Rothenberg E. Mol Biol Cell 31 859-865 (2020)
  6. The Ku complex: recent advances and emerging roles outside of non-homologous end-joining. Abbasi S, Parmar G, Kelly RD, Balasuriya N, Schild-Poulter C. Cell Mol Life Sci 78 4589-4613 (2021)
  7. DNA End Joining: G0-ing to the Core. Frock RL, Sadeghi C, Meng J, Wang JL. Biomolecules 11 1487 (2021)
  8. A Link between Replicative Stress, Lamin Proteins, and Inflammation. Willaume S, Rass E, Fontanilla-Ramirez P, Moussa A, Wanschoor P, Bertrand P. Genes (Basel) 12 552 (2021)
  9. Cytokines, JAK-STAT Signaling and Radiation-Induced DNA Repair in Solid Tumors: Novel Opportunities for Radiation Therapy. Hall WA, Sabharwal L, Udhane V, Maranto C, Nevalainen MT. Int J Biochem Cell Biol 127 105827 (2020)
  10. Druggable binding sites in the multicomponent assemblies that characterise DNA double-strand-break repair through non-homologous end joining. Kefala Stavridi A, Appleby R, Liang S, Blundell TL, Chaplin AK. Essays Biochem 64 791-806 (2020)
  11. DNA Repair in Haploid Context. Mourrain L, Boissonneault G. Int J Mol Sci 22 12418 (2021)
  12. Double-Stranded Break Repair in Mammalian Cells and Precise Genome Editing. Ali A, Xiao W, Babar ME, Bi Y. Genes (Basel) 13 737 (2022)
  13. Holding it together: DNA end synapsis during non-homologous end joining. Loparo JJ. DNA Repair (Amst) 130 103553 (2023)

Articles citing this publication (26)



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