Journal Article

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

Vertegaal, Alfred C. O., González-Prieto, Román, Singh, Jenny Kaur, Qian, Haibin, Smith, Rebecca, Lamers, Meindert, Kim, Robbert Q., Wiegant, Wouter W., van Attikum, Haico, de Groot, Anton J. L., Rother, Magdalena B., Huet, Sébastien, Vreeken, Kees, D’Augustin, Ostiane, Krawczyk, Przemek M.

2021

Overview

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. Classical non-homologous end-joining (cNHEJ) is the dominant pathway used by human cells to repair DNA double-strand breaks (DSBs) and maintain genome stability. Here the authors show that PARP1-driven chromatin expansion allows the recruitment of ZNF384, which in turn recruits Ku70/Ku80 to facilitate cNHEJ.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/106 / 13/109 / 13/31 / 13/44 / 13/89 / 14/19 / 14/32 / 14/35 / 14/63 / 14/69 / 38/22 / 38/23 / 38/70 / 38/71 / 45/29 / 45/77 / 631/337/1427/2191 / 631/45/612/1229 / 82/51 / 82/58 / 82/80 / 82/83 / Adapters / Adenosine diphosphate / Binding / Chromatin / Chromosome rearrangements / Damage / Deoxyribonucleic acid / DNA / DNA - metabolism / DNA Breaks, Double-Stranded / DNA damage / DNA repair / DNA-binding protein / Double-strand break repair / Genomes / Homology / Humanities and Social Sciences / Humans / Life Sciences / LIG4 protein / multidisciplinary / Mutation / N-Terminus / Non-homologous end joining / Poly(ADP-ribose) polymerase / Proteins / Recruitment / Repair / Science / Science (multidisciplinary) / Trans-Activators - genetics / Trans-Activators - metabolism / Transcription Factors - genetics / Transcription Factors - metabolism / Yeast / Zinc / Zinc finger proteins