The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure

Robert E. Turnbull, Louise Fairall, Almutasem Saleh, Emma Kelsall, Kyle L. Morris, T. J. Ragan, Christos G. Savva, Aditya Chandru, Christopher J. Millard, Olga V. Makarova, Corinne J. Smith, Alan M. Roseman, Andrew M. Fry, Shaun M. Cowley () and John W. R. Schwabe ()
Additional contact information
Robert E. Turnbull: University of Leicester
Louise Fairall: University of Leicester
Almutasem Saleh: University of Leicester
Emma Kelsall: University of Leicester
Kyle L. Morris: University of Warwick
T. J. Ragan: University of Leicester
Christos G. Savva: University of Leicester
Aditya Chandru: University of Leicester
Christopher J. Millard: University of Leicester
Olga V. Makarova: University of Leicester
Corinne J. Smith: University of Warwick
Alan M. Roseman: University of Manchester
Andrew M. Fry: University of Leicester
Shaun M. Cowley: University of Leicester
John W. R. Schwabe: University of Leicester

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.

Date: 2020
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DOI: 10.1038/s41467-020-17078-8

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