Phosphorylation of Histone H3 Thr-45 Is Linked to Apoptosis

Hurd, Paul J.; Bannister, Andrew J.; Halls, Karen; Dawson, Mark A.; Vermeulen, Michiel; Olsen, Jesper V.; Ismail, Heba; Somers, Joanna; Mann, Matthias; Owen-Hughes, Tom; Gout, Ivan; Kouzarides, Tony

doi:10.1074/jbc.m109.005421

Cited by 103 publications

(86 citation statements)

References 29 publications

(30 reference statements)

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“…Significance was estimated as in (B). While phosphorylation of the ShaDock may involve several kinases, including PKCd [35] or MSK1 [13], we showed that DYRK1A, mostly studied for its role in DS, positively regulates a number of immune gene promoters subject to HP1-mediated transcriptional repression. In fact, we found that DYRK1A positively regulates a very large number of inducible genes at which it may be required for maintenance of basal-level transcription.…”

Section: Discussionmentioning

confidence: 99%

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

et al. 2014

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Heterochromatin protein 1 (HP1) proteins are chromatin-bound transcriptional regulators. While their chromodomain binds histone H3 methylated on lysine 9, their chromoshadow domain associates with the H3 histone fold in a region involved in chromatin remodeling. Here, we show that phosphorylation at histone H3 threonine 45 and serine 57 within this latter region differentially affects binding of the three mammalian HP1 isoforms HP1a, HP1b and HP1c. Both phosphorylation events are dependent on the activity of the DYRK1A kinase that antagonizes HP1-mediated transcriptional repression and participates in abnormal activation of cytokine genes in Downs syndrome-associated megakaryoblastic leukemia.

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Section: Discussionmentioning

confidence: 99%

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

et al. 2014

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“…Snail1 also upregulates the binding of P-Thr45 histone H3 to the CDH1 promoter. The role of this phosphorylation has not been investigated yet; in mammalian cells the only report associates it with apoptosis (Hurd et al, 2009). It is possible that the modification is not linked to apoptosis per se but it is the consequence of the …”

Section: Akt2 Interacts With Snail1mentioning

confidence: 99%

Akt2 interacts with Snail1 in the E-cadherin promoter

et al. 2011

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Snail1 is a transcriptional factor essential for triggering epithelial-to-mesenchymal transition. Moreover, Snail1 promotes resistance to apoptosis, an effect associated to PTEN gene repression and Akt stimulation. In this article we demonstrate that Snail1 activates Akt at an additional level, as it directly binds to and activates this protein kinase. The interaction is observed in the nucleus and increases the intrinsic Akt activity. We determined that Akt2 is the isoform interacting with Snail1, an association that requires the pleckstrin homology domain in Akt2 and the C-terminal half in Snail1. Snail1 enhances the binding of Akt2 to the E-cadherin (CDH1) promoter and Akt2 interference prevents Snail1 repression of CDH1 gene. We also show that Snail1 binding increases Akt2 intrinsic activity on histone H3 and have identified Thr45 as a residue modified on this protein. Phosphorylation of Thr45 in histone H3 is sensitive to Snail1 and Akt2 cellular levels; moreover, Snail1 upregulates the binding of phosphoThr45 histone H3 to the CDH1 promoter. These results uncover an unexpected role of Akt2 in transcriptional control and point out to phosphorylation of Thr45 in histone H3 as a new epigenetic mark related to Snail1 and Akt2 action.

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“…Finally, there are some lesser known C-terminal phosphorylations of H3 that appear to play roles in cellular physiology. H3 Thr45 is phosphorylated by protein kinase C, and this modification is involved in apoptosis of cells in which DNA is nicked (57). Thr45 has also been reported to be phosphorylated in budding yeast by the kinase Cdc7-Dbf4.…”

Section: Histone H3mentioning

confidence: 99%

A Peek into the Complex Realm of Histone Phosphorylation

Banerjee

Chakravarti

2011

Molecular and Cellular Biology

168

111

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Although discovered long ago, posttranslational phosphorylation of histones has been in the spotlight only recently. Information is accumulating almost daily on phosphorylation of histones and their roles in cellular physiology and human diseases. An extensive cross talk exists between phosphorylation and other posttranslational modifications, which together regulate various biological processes, including gene transcription, DNA repair, and cell cycle progression. Recent research on histone phosphorylation has demonstrated that nearly all histone types are phosphorylated at specific residues and that these modifications act as a critical intermediate step in chromosome condensation during cell division, transcriptional regulation, and DNA damage repair. As with all young fields, apparently conflicting and sometimes controversial observations about histone phosphorylations and their true functions in different species are found in the literature. Accumulating evidence suggests that instead of functioning strictly as part of a general code, histone phosphorylation probably functions by establishing cross talk with other histone modifications and serving as a platform for recruitment or release of effector proteins, leading to a downstream cascade of events. Here we extensively review published information on the complexities of histone phosphorylation, the roles of proteins recognizing these modifications and the resuting physiological outcome, and, importantly, future challenges and opportunities in this fast-moving field.To fit the enormous length of the eukaryotic genome into the nucleus of a tiny cell requires some very sophisticated packaging. But this packaging must also be highly flexible and malleable so that the genome can be correctly replicated, transcribed, and finally translated. To meet these requirements, DNA is organized in a higher-order nucleoprotein complex known as chromatin. The basic unit of chromatin is the nucleosome, which is essentially DNA wrapped around a core of histone proteins. Each nucleosome is made up of an octamer of core histones (two each of H2A, H2B, H3, and H4), and around this histone core, the DNA is wrapped in two superhelical turns of 147 bp (67). Nucleosomes are spaced at intervals and linked by 20 to 60 bp of linker DNA to form an approximately 10-nm "beads on a string" structure, with H1 linker histones contacting the exit and entry points of the DNA strand that is spooled onto each nucleosome (141). Structurally, histones can be divided into the core domain, which makes up approximately 75% of the protein and is composed of histone fold motifs that physically interact with themselves to form the H2A/2B and H3/4 heterodimers, and the flexible tail domain, which makes up the remaining 25% of the protein.The tail domain is structurally undefined but has been found to be highly conserved. The tail domains are located at the amino termini of the four histones and the carboxyl terminus of H2A and are generally defined by their sensitivity to proteases.Nucleosomes are belie...

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Phosphorylation of Histone H3 Thr-45 Is Linked to Apoptosis

Cited by 103 publications

References 29 publications

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1‐mediated transcriptional repression

Akt2 interacts with Snail1 in the E-cadherin promoter

A Peek into the Complex Realm of Histone Phosphorylation

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