Mitotic catastrophe is the predominant response to histone acetyltransferase depletion.
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.
Ha
G-H
GH
Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Gyeonggi 440-746, Korea.
Kim
H-S
HS
Lee
C G
CG
Park
H-Y
HY
Kim
E-J
EJ
Shin
H-J
HJ
Lee
J-C
JC
Lee
K-W
KW
Lee
C-W
CW
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000502:physiology*; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology
D018797:Cell Cycle Proteins; C468783:H2AX protein, human; D006657:Histones; D011993:Recombinant Fusion Proteins; D051548:Histone Acetyltransferases