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The histone acetyltransferase component TRRAP is targeted for destruction during the cell cycle

Oncogene volume 33, pages 181–192 (2014)Cite this article

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Abstract

Chromosomes are dynamic structures that must be reversibly condensed and unfolded to accommodate mitotic division and chromosome segregation. Histone modifications are involved in the striking chromatin reconfiguration taking place during mitosis. However, the mechanisms that regulate activity and function of histone-modifying factors as cells enter and exit mitosis are poorly understood. Here, we show that the anaphase-promoting complex or cyclosome (APC/C) is involved in the mitotic turnover of TRRAP (TRansformation/tRanscription domain-Associated Protein), a common component of histone acetyltransferase (HAT) complexes, and that the pre-mitotic degradation of TRRAP is mediated by the APC/C ubiquitin ligase activators Cdc20 and Cdh1. Ectopic expression of both Cdh1 and Cdc20 reduced the levels of coexpressed TRRAP protein and induced its ubiquitination. TRRAP overexpression or stabilization induces multiple mitotic defects, including lagging chromosomes, chromosome bridges and multipolar spindles. In addition, lack of sister chromatid cohesion and impaired chromosome condensation were found after TRRAP overexpression or stabilization. By using a truncated form of TRRAP, we show that mitotic delay is associated with a global histone H4 hyperacetylation induced by TRRAP overexpression. These results demonstrate that the chromatin modifier TRRAP is targeted for destruction in a cell cycle-dependent fashion. They also suggest that degradation of TRRAP by the APC/C is necessary for a proper condensation of chromatin and proper chromosome segregation. Chromatin compaction mediated by histone modifiers may represent a fundamental arm for APC/C orchestration of the mitotic machinery.

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Acknowledgements

We thank Michael Cole for generous gift of the TRRAP expression vector. This work was supported by the Association pour la Recherche sur le Cancer (ARC), France, la Ligue Nationale (Française) Contre le Cancer (France), the Institut National du Cancer (INCA, France) and the Association for International Cancer Research (AICR), UK.

Author contributions

GI, HH-V, MM and M-PC performed all the experiments. MGF designed the TRRAP-GFP plasmids and performed the initial ubiquitination experiments. HH-V and ZH coordinated the project and wrote the manuscript. All authors discussed the results and manuscript text.

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  1. Z Herceg and H Hernandez-Vargas: Equal senior author contribution.

Authors and Affiliations

  1. Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France

    G Ichim, M Mola, M G Finkbeiner, M-P Cros, Z Herceg & H Hernandez-Vargas

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  1. G Ichim
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  2. M Mola
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  3. M G Finkbeiner
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Correspondence to Z Herceg or H Hernandez-Vargas.

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Ichim, G., Mola, M., Finkbeiner, M. et al. The histone acetyltransferase component TRRAP is targeted for destruction during the cell cycle. Oncogene 33, 181–192 (2014). https://doi.org/10.1038/onc.2012.570

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