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

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-Prieto, Alfred C. O. Vertegaal, Meindert Lamers, Sébastien Huet and Haico Attikum ()
Additional contact information
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
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
Haico Attikum: Leiden University Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26691-0

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