Suppression of centrosome duplication and amplification by deacetylases

Ling, Hongbo; Peng, Lirong; Seto, Edward; Fukasawa, Kenji

doi:10.4161/cc.21985

Cited by 26 publications

(29 citation statements)

References 39 publications

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“…Our data indicate that acetylation negatively regulates PLK4 kinase activity and thus prevents centrosome overamplification. This is in line with previous reports showing that lysine acetylation is detected at centrosomes by immunofluorescence using a pan-acetyl lysine antibody54. While we have described a role for the acetyltransferases KAT2A/2B in the regulation of centriole numbers, other studies have reported roles for lysine deacetylases (KDACs) in regulating centrosome function.…”

Section: Discussionsupporting

confidence: 93%

“…Moreover, it has been proposed that proteins involved in centrosome cohesion would be acetylated and substrates of these KDACs. This suggestion was further supported by localization studies showing that several KDACs, including KDAC1, localize at centrosomes54. The above findings notwithstanding, the exact mechanism for the regulation of centrosome architecture and/or numbers by KDACs is unclear.…”

Section: Discussionmentioning

confidence: 75%

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KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification

et al. 2016

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Lysine acetylation is a widespread post-translational modification regulating various biological processes. To characterize cellular functions of the human lysine acetyltransferases KAT2A (GCN5) and KAT2B (PCAF), we determined their acetylome by shotgun proteomics. One of the newly identified KAT2A/2B substrate is polo-like kinase 4 (PLK4), a key regulator of centrosome duplication. We demonstrate that KAT2A/2B acetylate the PLK4 kinase domain on residues K45 and K46. Molecular dynamics modelling suggests that K45/K46 acetylation impairs kinase activity by shifting the kinase to an inactive conformation. Accordingly, PLK4 activity is reduced upon in vitro acetylation of its kinase domain. Moreover, the overexpression of the PLK4 K45R/K46R mutant in cells does not lead to centrosome overamplification, as observed with wild-type PLK4. We also find that impairing KAT2A/2B-acetyltransferase activity results in diminished phosphorylation of PLK4 and in excess centrosome numbers in cells. Overall, our study identifies the global human KAT2A/2B acetylome and uncovers that KAT2A/2B acetylation of PLK4 prevents centrosome amplification.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 75%

KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification

et al. 2016

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“…centrosomal proteins, including c-tubulin, undergo acetylation and deacetylation to control their functions [36]. Deacetylation of c-tubulin could be required for MTOC congression into two poles because an increase in the number of c-tubulin foci occurs in RBBP4-depleted oocytes.…”

Section: Discussionmentioning

confidence: 99%

“…In mitosis, HDACs suppress centrosome overduplication [36]. Therefore, inhibiting histone deacetylation is accompanied by multipolar spindles and mitotic defects [37].…”

Section: Discussionmentioning

confidence: 99%

RBBP4 Regulates Histone Deacetylation and Bipolar Spindle Assembly During Oocyte Maturation in the Mouse1

Balboula¹,

Stein²,

Schultz³

et al. 2015

Biology of Reproduction

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During meiosis I (MI) in oocytes, the maturation-associated decrease of histone acetylation is critical for normal meiotic progression and accurate chromosome segregation. RBBP4 is a component of several different histone deacetylase containing chromatin-remodeling complexes, but RBBP4's role in regulating MI is not known. Depleting RBBP4 in mouse oocytes resulted in multipolar spindles at metaphase (Met) I with subsequent perturbed meiotic progression and increased incidence of abnormal spindles, chromosome misalignment, and aneuploidy at Met II. We attribute these defects to improper deacetylation of histones because histones H3K4, H4K8, H4K12, and H4K16 were hyperacetylated in RBBP4-depleted oocytes. Importantly, we show that RBBP4-mediated histone deacetylation is essential for regulating bipolar spindle assembly, at least partially, through promoting Aurora kinase (AURK) C function. To our knowledge, these results are the first to identify RBBP4 as a regulator of histone deacetylation during oocyte maturation, and they provide evidence that deacetylation is required for bipolar spindle assembly through AURKC.

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“…Myc-SIRT1 and GFP-SIRT1 expression vectors were generous gifts from Dr. Edward Seto 55,56 while transient transfections were carried out using PEI as we described before. 27 SIRT1 stable knockdown PC3 and 293T cells have been described previously.…”

Section: Plasmids Antibodies and Reagentsmentioning

confidence: 99%

Macromolecular crowding effect is critical for maintaining SIRT1's nuclear localization in cancer cells

Sun

Fang

2016

Cell Cycle

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SIRT1 is a principle class III histone deacetylase which exhibits versatile functions in stress response, development, and pathological processes including cancer. Although SIRT1 deacetylates a wide range of nuclear and cytoplasmic proteins, its subcellular localization in cancer cells has been controversial. In this study, we uncovered the inconsistent reports about SIRT1 subcellular localization is partially due to different analysis approaches. While immunofluorescence and live cell imaging reveal a predominant nuclear localization of SIRT1, conventional cell fractionation often results in a severe leaking of SIRT1 into the cytoplasm. Such a leakage is mainly caused by loss of cytoplasmic macromolecular crowding effect as well as hypotonic dwelling during the isolation of the nuclei. We also developed an improved cell fractionation procedure which maintains SIRT1 in its original subcellular localization. Analyzing a variety of human cancer cell lines using this approach and other methods demonstrate that SIRT1 predominantly localizes to the nucleus in cancer cells.

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Suppression of centrosome duplication and amplification by deacetylases

Cited by 26 publications

References 39 publications

KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification

KAT2A/KAT2B-targeted acetylome reveals a role for PLK4 acetylation in preventing centrosome amplification

RBBP4 Regulates Histone Deacetylation and Bipolar Spindle Assembly During Oocyte Maturation in the Mouse1

Macromolecular crowding effect is critical for maintaining SIRT1's nuclear localization in cancer cells

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