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Zinc finger protein ZNF384 is an adaptor of Ku to DNA during classical non-homologous end-joining

Author

Listed:
  • Jenny Kaur Singh

    (Leiden University Medical Center)

  • Rebecca Smith

    (Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)—UMR 6290)

  • Magdalena B. Rother

    (Leiden University Medical Center)

  • Anton J. L. Groot

    (Leiden University Medical Center)

  • Wouter W. Wiegant

    (Leiden University Medical Center)

  • Kees Vreeken

    (Leiden University Medical Center)

  • Ostiane D’Augustin

    (Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)—UMR 6290
    Université Paris-Saclay, Université de Paris, CEA)

  • Robbert Q. Kim

    (Leiden University Medical Center)

  • Haibin Qian

    (Amsterdam University Medical Centers (location AMC), Cancer Center Amsterdam)

  • Przemek M. Krawczyk

    (Amsterdam University Medical Centers (location AMC), Cancer Center Amsterdam)

  • Román González-Prieto

    (Amsterdam University Medical Centers (location AMC), Cancer Center Amsterdam)

  • Alfred C. O. Vertegaal

    (Amsterdam University Medical Centers (location AMC), Cancer Center Amsterdam)

  • Meindert Lamers

    (Amsterdam University Medical Centers (location AMC), Cancer Center Amsterdam)

  • Sébastien Huet

    (Univ Rennes, CNRS, IGDR (Institut de génétique et développement de Rennes)—UMR 6290
    Institut Universitaire de France)

  • Haico Attikum

    (Leiden University Medical Center)

Abstract

DNA double-strand breaks (DSBs) are among the most deleterious types of DNA damage as they can lead to mutations and chromosomal rearrangements, which underlie cancer development. Classical non-homologous end-joining (cNHEJ) is the dominant pathway for DSB repair in human cells, involving the DNA-binding proteins XRCC6 (Ku70) and XRCC5 (Ku80). Other DNA-binding proteins such as Zinc Finger (ZnF) domain-containing proteins have also been implicated in DNA repair, but their role in cNHEJ remained elusive. Here we show that ZNF384, a member of the C2H2 family of ZnF proteins, binds DNA ends in vitro and is recruited to DSBs in vivo. ZNF384 recruitment requires the poly(ADP-ribosyl) polymerase 1 (PARP1)-dependent expansion of damaged chromatin, followed by binding of its C2H2 motifs to the exposed DNA. Moreover, ZNF384 interacts with Ku70/Ku80 via its N-terminus, thereby promoting Ku70/Ku80 assembly and the accrual of downstream cNHEJ factors, including APLF and XRCC4/LIG4, for efficient repair at DSBs. Altogether, our data suggest that ZNF384 acts as a ‘Ku-adaptor’ that binds damaged DNA and Ku70/Ku80 to facilitate the build-up of a cNHEJ repairosome, highlighting a role for ZNF384 in DSB repair and genome maintenance.

Suggested Citation

  • Jenny Kaur Singh & Rebecca Smith & Magdalena B. Rother & Anton J. L. Groot & Wouter W. Wiegant & Kees Vreeken & Ostiane D’Augustin & Robbert Q. Kim & Haibin Qian & Przemek M. Krawczyk & Román González, 2021. "Zinc finger protein ZNF384 is an adaptor of Ku to DNA during classical non-homologous end-joining," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26691-0
    DOI: 10.1038/s41467-021-26691-0
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    References listed on IDEAS

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