Histone H3 Thr-3 Phosphorylation by Haspin Positions Aurora B at Centromeres in Mitosis

Wang, Fangwei; Dai, Jun; Daum, John R.; Niedzialkowska, E.; Banerjee, Budhaditya; Stukenberg, P. Todd; Gorbsky, Gary J.; Higgins, Jonathan M.G.

doi:10.1126/science.1189435

Cited by 441 publications

(586 citation statements)

References 31 publications

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“…It requires Haspin-dependent phosphorylation of histone H3 at Thr3 (H3-T3ph) and Bub1-dependent phosphorylation of histone H2A at Thr120 (H2A-T120ph). H3-T3ph binds the Survivin subunit of the CPC and H2A-T120ph interacts with Borealin through a Shugoshin (Sgo) intermediate [16][17][18]. The signals upstream of these two converging centromere recruitment pathways are now beginning to emerge.…”

Section: Introductionmentioning

confidence: 99%

Mps1 promotes rapid centromere accumulation of Aurora B

et al. 2012

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Aurora B localization to mitotic centromeres, which is required for proper chromosome alignment during mitosis, relies on Haspin‐dependent histone H3 phosphorylation and on Bub1‐dependent histone H2A phosphorylation—which interacts with Borealin through a Shugoshin (Sgo) intermediate. We demonstrate that Mps1 stimulates the latter recruitment axis. Mps1 activity enhances H2A‐T120ph and is critical for Sgo1 recruitment to centromeres, thereby promoting Aurora B centromere recruitment in early mitosis. Importantly, chromosome biorientation defects caused by Mps1 inhibition are improved by restoring Aurora B centromere recruitment. As Mps1 kinetochore localization reciprocally depends on Aurora B, we propose that this Aurora B‐Mps1 recruitment circuitry cooperates with the Aurora B‐Haspin feedback loop to ensure rapid centromere accumulation of Aurora B at the onset of mitosis.

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Section: Introductionmentioning

confidence: 99%

Mps1 promotes rapid centromere accumulation of Aurora B

et al. 2012

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“…Recently, it was reported that phosphorylation of histone H3 threonine 3 (H3T3ph) by Haspin is required for recruiting Aurora B protein kinase, an enzyme essential for accurate chromosome inheritance, to chromosomes that are poised to segregate into daughter cells (41,42). In addition, phosphorylation at threonine 6 (H3T6ph) by PKC␤ I plays a key role in preventing LSD1 from demethylating H3K4 but not from demethylating H3K9 during AR-dependent gene activation (43).…”

Section: Volume 286 • Number 42 • October 21 2011mentioning

confidence: 99%

Recognition of Unmodified Histone H3 by the First PHD Finger of Bromodomain-PHD Finger Protein 2 Provides Insights into the Regulation of Histone Acetyltransferases Monocytic Leukemic Zinc-finger Protein (MOZ) and MOZ-related factor (MORF)

Jin

Zhang

et al. 2011

Journal of Biological Chemistry

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MOZ (monocytic leukemic zinc-finger protein) and MORF (MOZ-related factor) are histone acetyltransferases important for HOX gene expression as well as embryo and postnatal development. They form complexes with other regulatory subunits through the scaffold proteins BRPF1/2/3 (bromodomain-PHD (plant homeodomain) finger proteins 1, 2, or 3). BRPF proteins have multiple domains, including two PHD fingers, for potential interactions with histones. Here we show that the first PHD finger of BRPF2 specifically recognizes the N-terminal tail of unmodified histone H3 (unH3) and report the solution structures of this PHD finger both free and in complex with the unH3 peptide. Structural analysis revealed that the unH3 peptide forms a third antiparallel ␤-strand that pairs with the PHD1 two-stranded antiparallel ␤-sheet. The binding specificity was determined primarily through the recognition of arginine 2 and lysine 4 of the unH3 by conserved aspartic acids of PHD1 and of threonine 6 of the unH3 by a conserved asparagine. Isothermal titration calorimetry and NMR assays showed that post-translational modifications such as H3R2me2as, H3T3ph, H3K4me, H3K4ac, and H3T6ph antagonized the interaction between histone H3 and PHD1. Furthermore, histone binding by PHD1 was important for BRPF2 to localize to the HOXA9 locus in vivo. PHD1 is highly conserved in yeast NuA3 and other histone acetyltransferase complexes, so the results reported here also shed light on the function and regulation of these complexes.Histone acetyltransferases (HATs) 3 are enzymes that catalyze the transfer of an acetyl group from acetyl-CoA to the ⑀-amino groups of lysine on histones, which results in important regulatory effects in chromatin structure and assembly as well as gene expression. HATs are highly diverse and generally form multiprotein complexes. Different HAT complexes are composed of various unique subunits, and the combination of these subunits contributes to the unique features of each HAT complex (1).MOZ (monocytic leukemic zinc-finger protein) and MORF (MOZ-related factor), a pair of large HATs of the MYST (Moz, Ybf2/Sas3, Sas2, Tip60) family, are important for hematopoiesis, skeletogenesis, neurogenesis, and other developmental processes, and they also have been implicated in leukemogenic and other tumorigenic progressions (2). A recent study in mice embryos reported that MOZ is required for normal levels of spatially correct Hox gene expression and for correct body segment identity. MOZ is specifically required for the H3K9 acetylation of active Hox gene loci (3). MOZ is also required for the maintenance of hematopoietic stem cells and plays a role in the differentiation of erythroid and myeloid cells (4). By contrast, MORF is required for the maintenance of undifferentiated neuronal progenitors and for adult neural stem cell self-renewal and neuronal differentiation (5). MOZ and MORF genes are often translocated in acute myeloid leukemia cells, producing either fusion proteins with CBP (cAMP-response elementbinding protein (CREB)-bind...

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“…Activated Plk1 phosphorylates several sites on Haspin N-terminus releasing its activity in a timely manner at the beginning of mitosis triggering H3T3 phosphorylation and CPC recruitment at centromeres [47,48]. Furthermore, Wang et al showed that Aurora B further phosphorylates Haspin Nterminus enhancing its ability to generate H3T3 phospho-sites for Survivin/CPC binding [49] ( Figure 5 lower panel). Another recent study showed that Aurora A also phosphorylates Haspin N-terminus triggering the Aurora B/Haspin feedback loop [50].…”

Section: Regulation Of Haspin Activitymentioning

confidence: 98%

The Mitotic Protein Kinase Haspin and Its Inhibitors

Feizbakhsh¹,

Place²,

Fant³

et al. 2017

Protein Phosphorylation

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Haspin is an atypical serine/threonine protein kinase essential to mitosis. Unlike other protein kinases, its kinase domain does not require phosphorylation in order to be activated and bears very high substrate specificity and selectivity. Few substrates have been identified so far. Haspin phosphorylation on threonine 3 of Histone H3 from prophase to anaphase participates to centromeric Aurora B localization and ensures proper kinetochore-microtubule attachment. Haspin is also involved in the maintenance of centromeric cohesion and the mitotic spindle. Inhibitors have been developed and provided tools to dissect Haspin function. The kinase is now considered as a potential therapeutic target against cancer. We discuss here the latest findings on this essential mitotic protein.

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Histone H3 Thr-3 Phosphorylation by Haspin Positions Aurora B at Centromeres in Mitosis

Cited by 441 publications

References 31 publications

Mps1 promotes rapid centromere accumulation of Aurora B

Mps1 promotes rapid centromere accumulation of Aurora B

Recognition of Unmodified Histone H3 by the First PHD Finger of Bromodomain-PHD Finger Protein 2 Provides Insights into the Regulation of Histone Acetyltransferases Monocytic Leukemic Zinc-finger Protein (MOZ) and MOZ-related factor (MORF)

The Mitotic Protein Kinase Haspin and Its Inhibitors

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