Brd4 is required for recovery from antimicrotubule drug-induced mitotic arrest: preservation of acetylated chromatin.
The mammalian bromodomain protein Brd4 interacts with mitotic chromosomes by binding to acetylated histone H3 and H4 and is thought to play a role in epigenetic memory. Mitotic cells are susceptible to antimicrotubule drugs. These drugs activate multiple response pathways and arrest cells at mitosis. We found that Brd4 was rapidly released from chromosomes upon treatment with antimicrotubule drugs, including the reversible agent nocodazole. Yet, when nocodazole was withdrawn, Brd4 was reloaded onto chromosomes, and cells proceeded to complete cell division. However, cells in which a Brd4 allele was disrupted (Brd4+/-), and expressing only half of the normal Brd4 levels, were defective in reloading Brd4 onto chromosomes. Consequently, Brd4+/- cells were impaired in their ability to recover from nocodazole-induced mitotic arrest: a large fraction of +/- cells failed to reach anaphase after drug withdrawal, and those that entered anaphase showed an increased frequency of abnormal chromosomal segregation. The reloading defect observed in Brd4+/- cells coincided with selective hypoacetylation of lysine residues on H3 and H4. The histone deacetylase inhibitor trichostatin A increased global histone acetylation and perturbed nocodazole-induced Brd4 unloading. Brd4 plays an integral part in a cellular response to drug-induced mitotic stress by preserving a properly acetylated chromatin status.
Nishiyama
Akira
A
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-2753, USA.
Dey
Anup
A
Miyazaki
Jun-Ichi
J
Ozato
Keiko
K
D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism*; D020090:Chromosome Segregation / Q000187:drug effects; D019926:Cyclin B / Q000502:physiology; D056744:Cyclin B1; D006579:Heterozygote; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology; D009153:Mutagens / Q000494:pharmacology; D015739:Nocodazole / Q000494:pharmacology*; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D011123:Polyploidy; D014157:Transcription Factors; D000092468:Bromodomain Containing Proteins
D016203:CDC2 Protein Kinase; D002843:Chromatin; D019926:Cyclin B; D056744:Cyclin B1; D006657:Histones; D006877:Hydroxamic Acids; D009153:Mutagens; D015739:Nocodazole; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; C012589:trichostatin A