The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure
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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.
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Knockdown of MIDEAS or DNTTIP1 in cancer cells leads to misalignment of chromosomes during mitosis.
“Indeed, knockdown of MIDEAS or DNTTIP1 in cancer cells leads to misalignment of chromosomes during mitosis.(Turnbull et al., 2020).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Turnbull et al., 2020
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Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs)
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- Authors
- Turnbull, R. E., Fairall, L., Saleh, A., Kelsall, E., Morris, K. L., Ragan, T. J., Savva, C. G., Chandru, A., Millard, C. J., Makarova, O. V., Smith, C. J., Roseman, A. M., Fry, A. M., Cowley, S. M., & Schwabe, J. W. R.
- Affiliations
- University of Leicester (GB)
- AstraZeneca (United Kingdom) (GB)
- Hammersmith Hospital (GB)
- University of Warwick (GB)
- University of Manchester (GB)
- Corresponding author
- Cowley, Shaun M.
- Schwabe, John W. R.
- ORCID
- Venue
- Nature Communications
- Published
- 2020-06-26
- Volume
- 11
- Issue
- 1
- Pages
- 3252-3252
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC7319964
- OpenAlex
- W3037025246
- Cited by
- 108
- References
- 55
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 15 · 2023: 16 · 2022: 14 · 2021: 29 · 2020: 10
- FWCI
- 5.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Research Explorer (The University of Manchester) (submittedVersion, other-oa)
- Spiral (Imperial College London) (submittedVersion, other-oa)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Apollo
- Funders
- Wellcome Trust (100237/Z/12/Z)
- RCUK | Biotechnology and Biological Sciences Research Council (BB/N002954/1)
- RCUK | Medical Research Council (MC_PC_17136)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- histone deacetylase complex, class I HDACs, HDAC1, embryonic development, chromosome alignment, mitosis, cardiac anomalies, cryo-EM structure, complex assembly, gene expression regulation
- MeSH terms
- Protein Domains, Amino Acid Sequence, Animals, Cell Line, Chromatin, Embryo, Mammalian, Fibroblasts, Heterozygote, Histone Deacetylases, Homozygote, Humans, Mice, Inbred C57BL, Mitosis, Models, Molecular, Nuclear Proteins, Mice, Knockout, Chromosomes, Mammalian, Multiprotein Complexes, Embryonic Development, Gene Regulatory Networks, Protein Multimerization
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