ZNF512B binds RBBP4 via a variant NuRD interaction motif and aggregates chromatin in a NuRD complex-independent manner

  • Nucleic Acids Res. 2024 Nov 27;52(21):12831-12849. doi: 10.1093/nar/gkae926.
Tim Marius Wunderlich  1 ,  Chandrika Deshpande  2 ,  Lena W Paasche  1 ,  Tobias Friedrich  3 ,  Felix Diegmüller  1 ,  Elias Haddad  1 ,  Carlotta Kreienbaum  1 ,  Haniya Naseer  1 ,  Sophie E Stebel  1 ,  Nadine Daus  1 ,  Jörg Leers  1 ,  Jie Lan  1 ,  Van Tuan Trinh  4 ,  Olalla Vázquez  4  5 ,  Falk Butter  6  7 ,  Marek Bartkuhn  3 ,  Joel P Mackay  2 ,  Sandra B Hake  1
Affiliations
  • 1. Institute for Genetics, Justus-Liebig University Giessen, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany.
  • 2. School of Life and Environmental Sciences, Butlin Ave, University of Sydney, Darlington, New South Wales 2006, Australia.
  • 3. Biomedical Informatics and Systems Medicine Science Unit for Basic and Clinical Medicine, Justus-Liebig University Giessen, Aulweg 128, 35392 Giessen, Germany.
  • 4. Department of Chemistry, Philipps University Marburg, Hans-Meerwein-Straße 4, 35043 Marburg, Germany.
  • 5. Center for Synthetic Microbiology, Philipps University Marburg, Karl-von-Frisch-Str. 14, 35043 Marburg, Germany.
  • 6. Institute of Molecular Biology (IMB), Ackermannweg 4, 55128 Mainz, Germany.
  • 7. Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institute, Federal Research Institute for Animal Health, Südufer 10, 17493 Greifswald, Germany.
PMID: 39460621 DOI: 10.1093/nar/gkae926
Abstract

The evolutionarily conserved histone variant H2A.Z plays a crucial role in various DNA-based processes, but the mechanisms underlying its activity are not completely understood. Recently, we identified the zinc finger (ZF) protein ZNF512B as a protein associated with H2A.Z, HMG20A and PWWP2A. Here, we report that high levels of ZNF512B expression lead to nuclear protein and chromatin aggregation foci that form in a manner that is dependent on the ZF domains of ZNF512B. Notably, we demonstrate ZNF512B binding to the nucleosome remodeling and deacetylase (NuRD) complex. We discover a conserved amino acid sequence within ZNF512B that resembles the NuRD-interaction motif (NIM) previously identified in FOG-1 and other transcriptional regulators. By solving the crystal structure of this motif bound to the NuRD component RBBP4 and by applying several biochemical and biophysical assays, we demonstrate that this internal NIM is both necessary and sufficient for robust and high-affinity NuRD binding. Transcriptome analyses and reporter assays identify ZNF512B as a repressor of gene expression that can act in both NuRD-dependent and -independent ways. Our study might have implications for diseases in which ZNF512B expression is deregulated, such as Cancer and neurodegenerative diseases, and hints at the existence of more proteins as potential NuRD interactors.