Abstract
Histone acetylation induces chromatin opening by perturbing higher-order chromatin compaction and folding, suggesting that histone acetylation and deacetylation dynamics are central to chromosome condensation or decondensation. The condensation of chromosomes during mitosis is an essential prerequisite for successful chromosome segregation. In this study, we depleted three representative histone acetyltransferases (HATs; p300, CBP, and P/CAF) using shRNAs to explore their role in regulating mitotic progression and chromosome segregation. We showed that HAT depletion severely interfered with the normal timing of mitotic progression, and it reduced condensin subunit levels. The predominant response to HAT depletion, in both human primary and cancer cells, was a mitotic catastrophe following aberrant mitotic arrest. Alternatively, adaptation to HAT depletion, particularly in cancer cells, led to multinucleation and aneuploidy. Interestingly, mitotic catastrophe induced by HAT depletion appeared to be coupled to the signaling process of H2AX phosphorylation and foci formation, independently of DNA double-strand breaks and DNA damage. Taken together, our results provide novel molecular evidence that HAT proteins maintain mitotic chromatin assembly and integrity as a cellular determinant of mitotic cell death.
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Abbreviations
- HDAC:
-
histone deacetylases
- HAT:
-
histone acetyltransferase
- phospho-H3:
-
phosphorylated histone H3
- KD:
-
knockdown
- GFP:
-
green fluorescence protein
- rAd:
-
recombinant adenovirus
- PLA:
-
processed lipoaspirate
- SMC:
-
structural maintenance of chromosomes
- NR:
-
nocodazole treatment
- ATM:
-
ataxia telangiectasia-mutated
- Trrap:
-
transformation/transcription domain-associated protein
- Luc:
-
luciferase
- qRT-PCR:
-
quantitative real-time PCR
- DMEM:
-
Dulbecco's modified Eagle's medium
- FBS:
-
fetal bovine serum
- bFGF:
-
basic fibroblast growth factor
- PBS:
-
phosphate-buffered saline
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Acknowledgements
We thank Dr. Seong Tae Kim for comments on the manuscript. This study was supported by research grants from the Korea Research Foundation (KRF-2006-C00324), the 21C Frontier Functional Human Genome Project from the Ministry of Science and Technology in Korea (FG07-21-01), and the Korea Science and Engineering Foundation through the Rheumatism Research Center (RII-2002-098-05003, 2007).
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Supplementary Information accompanies the paper on Cell Death and Differentiation website (http://www.nature.com/cdd)
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Ha, GH., Kim, HS., Lee, C. et al. Mitotic catastrophe is the predominant response to histone acetyltransferase depletion. Cell Death Differ 16, 483–497 (2009). https://doi.org/10.1038/cdd.2008.182
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DOI: https://doi.org/10.1038/cdd.2008.182
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