The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment

Dai, Jun; Sultan, Sammy; Taylor, Stephen S.; Higgins, Jonathan M.G.

doi:10.1101/gad.1267105

Cited by 350 publications

(538 citation statements)

References 56 publications

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“…The following plasmids were described previously: pSG5-AR, GST-AR-NTD, GST-AR-DBD, GST-AR-LBD, pCMX-flag, pCMV-flag-PRK1 K644E, pcDNA3-myc-ΔNPRK1, TK-LUC, MMTV-LUC, Probasin-LUC, and PSA-LUC6; MBP-JMJD2C, His-JMJD2C, and pCMX-flag-JMJD2C4, GST-LSD1 and pCMX-flag-LSD13, GST-H3 1-44 15 . To construct pLenti6-miRNA1-PRK1, pLenti6-miRNA2-PRK1, pGW-miRNA1-PRK1, and pGWmiRNA2-PRK1, the DNA corresponding to miRNA1-PRK1 (5'-TGCTGATTGCTGTAGGTCTGGATCATGTTTTGGCCACTGACTGACATGATCCACC TACAGCAAT-3' and 5'-CCTGATTGCTGTAGGTGGATCATGTCAGTCAGTGGCCAAAACATGATCCAGACC TACAGCAATC-3') and miRNA2-PRK1 (5'-TGCTGTTACTGTCCTGCAACATCTGCGTTTTGGCCACTGACTGACGCAGATGTCA GGACAGTAA-3' and 5'-CCTGTTACTGTCCTGACATCTGCGTCAGTCAGTGGCCAAAACGCAGATGTTGCA GGACAGTAAC-3') was cloned into pLenti6/V5-DEST and pcDNA-6.2-GW-EmGFP according to the manufacturer's instructions (Invitrogen).…”

Section: Plasmidsmentioning

confidence: 99%

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Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation

et al. 2007

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Posttranslational modifications of histones such as methylation, acetylation, and phosphorylation regulate chromatin structure and gene expression. Here we show that protein kinase C-related kinase 1 (PRK1) phosphorylates histone H3 at threonine 11 (H3T11) upon ligand-dependent recruitment to androgen receptor (AR) target genes. PRK1 is pivotal to AR function since PRK1 knockdown or inhibition impedes AR-dependent transcription. Blocking PRK1 function abrogates androgen-induced H3T11 phosphorylation, and inhibits androgen-induced demethylation of histone H3. Moreover, serine 5-phosphorylated RNA polymerase II is no longer observed at AR target promoters. Phosphorylation of H3T11 by PRK1 accelerates demethylation by the Jumonji C (JmjC) domain-containing protein JMJD2C. Thus, phosphorylation of H3T11 by PRK1 establishes a novel chromatin mark for gene activation, identifying PRK1 as a gatekeeper of ARdependent transcription. Importantly, levels of PRK1 and phosphorylated H3T11 correlate with Gleason scores of prostate carcinomas. Finally, inhibition of PRK1 blocks AR-induced tumour cell proliferation, making PRK1 a promising therapeutic target. Keywords PRK1; androgen receptor; histone phosphorylation; prostate cancerThe N-terminal tails of histones are subject to a plethora of posttranslational modifications such as methylation, acetylation, and phosphorylation by specific chromatin-modifying enzymes1. During gene expression, these modifications influence chromatin structure to facilitate the assembly of the RNA polymerase II transcription machinery1 , 2. Androgen receptor (AR)-dependent gene expression is characterized by changes in chromatin

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Section: Plasmidsmentioning

confidence: 99%

“…To construct GST-H3 1-15, GST-H3 1-15 T11A, GST-H3 16-30, and GST-H3 29-44, the corresponding cDNA fragments were cloned into pGEX4T1. To construct GST-H3 1-135 and GST H3 1-135 T11A the corresponding cDNA fragments were cloned into pET-GEX 15 . Cloning details can be obtained upon request.…”

Section: Plasmidsmentioning

confidence: 99%

Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation

et al. 2007

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“…Histone H3 was the first Haspin substrate to be identified. It is specifically phosphorylated on Thr3 [8,10,13]. This phosphorylation (H3T3ph) was demonstrated both in vitro and in several cell lines by immunofluorescence, using histone H3 Thr3 phospho-specific antibodies ( Figure 5 upper panel).…”

Section: Haspin Substratesmentioning

confidence: 85%

“…Haspin is constitutively expressed throughout the cell cycle, unlike other mitotic kinases such as Aurora B and Plk1, which are degraded at the end of mitosis [13,24,25]. So far, the precise cellular localization of the endogenous protein could not be determined due to lack of immunofluorescence-specific antibodies to Haspin.…”

Section: Haspin Localizationmentioning

confidence: 99%

“…So far, the precise cellular localization of the endogenous protein could not be determined due to lack of immunofluorescence-specific antibodies to Haspin. However, several overexpression studies have reported localization of GFP-or Myc-tagged Haspin in different eukaryotic cell lines (HeLa, U-2 OS, Hek293, COS-7) using time-lapse video microscopy or immunofluorescence staining techniques or time-lapse video microscopy [4,13]. All these studies showed that Haspin localizes in discrete foci and nucleoli in the nucleus during interphase.…”

Section: Haspin Localizationmentioning

confidence: 99%

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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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Histones: Gene Organisation and Post‐translational Modification

Doenecke

2014

Encyclopedia of Life Sciences

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Histones are highly conserved basic proteins that form the major part of the protein moiety of eukaryotic chromosomes. Together with deoxyribonucleic acid (DNA) , they organise the repeat unit of chromatin, the nucleosome, which consists of a deoxyribonucleoprotein core particle and linker DNA connecting these core units. The core particle is composed of 147 nucleotide pairs of DNA and two copies of each of the four core histones H2A, H2B, H3 and H4. The DNA linking core particles is associated with one copy of a fifth histone type termed H1. The basal organisation of chromatin as a histone–DNA complex implies that histones functionally participate in the regulation of chromatin‐bound processes, such as transcription, DNA repair or DNA replication. Post‐translational modification of histone amino acid side chains or replacement of canonical histones by nonallelic variants and recognition of such modified sites by regulatory factors are key processes in modulating the functional organisation of chromatin. Key Concepts: The histone family of basic chromosome consists of five protein classes that organise together with DNA the nucleosome, the basic chromatin unit. Two copies of each of the four histones H2A, H2B, H3 and H4 form together with DNA the nucleosome core particle; linker DNA and histone H1 complete the nucleosome as the chromosomal repeat unit. The five canonical histones are extremely conserved proteins, and the nucleosome structure is essentially the same from unicellular to vertebrate species. Nonallelic variants of four of the five histones (the exception is H4) can replace the canonical isoforms, thereby mediating dynamic changes of chromatin structure and function. Histones are post‐translationally modified by, for example, acetylation of lysine residues, methylation of lysine or arginine residues and phosphorylation of hydroxyl groups in side chains of serine, threonine or tyrosine. Such modified side chains (and combinations thereof) provide interaction sites for binding of factors involved in chromatin‐bound processes. Histone H1 is also termed linker histones, because it interacts with the DNA linking nucleosome core particles. Yeast has just one type of H1‐like histones, whereas mammals have several nonallelic H1 variants. H1 is involved in the formation of higher order chromatin structures above the level of arrays of nucleosomes.

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The kinase haspin is required for mitotic histone H3 Thr 3 phosphorylation and normal metaphase chromosome alignment

Cited by 350 publications

References 56 publications

Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation

Phosphorylation of histone H3 at threonine 11 establishes a novel chromatin mark for transcriptional regulation

The Mitotic Protein Kinase Haspin and Its Inhibitors

Histones: Gene Organisation and Post‐translational Modification

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