Diminishing HDACs by drugs or mutations promotes normal or abnormal sister chromatid separation by affecting APC/C and adherin.
Histone acetyltransferases (HATs) and histone deacetylases (HDACs) play important roles in cell regulation, including cell cycle progression, although their precise role in mitotic progression remains elusive. To address this issue, the effects of HDAC inhibition were examined upon a variety of mitotic mutants of the fission yeast Schizosaccharomyces pombe, which contains three HDACs that are sensitive to trichostatin A (TSA) and are similar to human HDACs. Here it is shown that HDACs are implicated in sister chromatid cohesion and separation. A mutant of the cohesin loader Mis4 (adherin) was hypersensitive to TSA and synthetically lethal with HDAC deletion mutations. TSA treatment of mis4 mutant cells decreased chromatin-bound cohesins in the chromosome arm region. By contrast, HDAC inhibitors and clr6 HDAC mutations rescued temperature sensitive (ts) phenotypes of the mutants of the ubiquitin ligase complex anaphase-promoting complex/cyclosome (APC/C), which display metaphase arrest. This suppression coincided with facilitated complex formation of APC/C. Moreover, our mass spectrometry analysis showed that an APC/C subunit, Cut23/APC8, is acetylated. HATs and HDACs might directly target adherin and APC/C to ensure proper chromosome segregation, and anti-tumour effects of HDAC inhibitors could be attributed to this deregulation.
Kimata
Yuu
Y
CREST Research Program, Japan Science and Technology Corporation, Graduate School of Biostudies, Kyoto University, Yoshida-Honmachi, Kyoto 606-8501, Japan.
Matsuyama
Akihisa
A
Nagao
Koji
K
Furuya
Kanji
K
Obuse
Chikashi
C
Yoshida
Minoru
M
Yanagida
Mitsuhiro
M
D064173:Anaphase-Promoting Complex-Cyclosome; D002842:Chromatids / Q000187:drug effects / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D013058:Mass Spectrometry; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009154:Mutation; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D012854:Sister Chromatid Exchange / Q000187:drug effects; D043743:Ubiquitin-Protein Ligase Complexes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D005656:Fungal Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D006655:Histone Deacetylases