Abstract
The transactivation/transformation–domain associated protein (TRRAP) belongs to the Ataxia-telangiectasia mutated (ATM) super-family and has been identified as a cofactor for c-MYC–mediated oncogenic transformation1,2,3. TRRAP and its yeast homolog (Tra1p) are components of histone acetyltransferase (HAT) complexes, SAGA (refs. 2,4,5), PCAF (ref. 3) and NuA4 (ref. 6), which are important for the regulation of transcription and cell cycle progression7,8 and also have a role in cell viability1,2. Yet the biological function of this molecule and how it controls proliferation are still unclear. Here we show that null mutation of Trrap in mice results in peri-implantation lethality due to a blocked proliferation of blastocysts. We use an inducible Cre-loxP system to show that loss of Trrap blocks cell proliferation because of aberrant mitotic exit accompanied by cytokinesis failure and endoreduplication. Trrap-deficient cells fail to sustain mitotic arrest despite chromosome missegregation and disrupted spindles, and display compromised cdk1 activity. Trrap is therefore essential for early development and required for the mitotic checkpoint and normal cell cycle progression.
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Acknowledgements
We thank E.F. Wagner (IMP, Vienna, Austria) for kindly providing plasmids and reagents, and P. Chambon (Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France) for the pCre-ER plasmid. We also thank M.-P. Cros for the maintenance of mouse colonies and assistance in collecting blastocysts from Trrap mutant mice, W.-M. Tong for instruction on analysis of embryonic lethality, V. Petrilli for help in immortalization of MEFs and H. Li for preparation of kinase assays. We are also grateful to J. Bradbury, M. Glotzer, E. Passague, J.M. Peters, E. Van Dyck, and E.F. Wagner for critical comments and discussions. Further thanks are due to J. Cheney and E. El-Akroud for editing the manuscript. Work carried out in the laboratory of S.J. was funded by the Cancer Research Campaign.
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Herceg, Z., Hulla, W., Gell, D. et al. Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. Nat Genet 29, 206–211 (2001). https://doi.org/10.1038/ng725
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DOI: https://doi.org/10.1038/ng725
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