Phosphorylation of histone H3 Thr-45 is linked to apoptosis.
Numerous post-translational modifications have been identified in histones. Most of these occur within the histone tails, but a few have been identified within the histone core sequences. Histone core post-translational modifications have the potential to directly modulate nucleosome structure and consequently DNA accessibility. Here, we identify threonine 45 of histone H3 (H3T45) as a site of phosphorylation in vivo. We find that phosphorylation of H3T45 (H3T45ph) increases dramatically in apoptotic cells, around the time of DNA nicking. To further explore this connection, we analyzed human neutrophil cells because they are short-lived cells that undergo apoptosis in vivo. Freshly isolated neutrophils contain very little H3T45ph, whereas cells cultured for 20 h possess significant amounts; the kinetics of H3T45ph induction closely parallel those of caspase-3 activation. Cytokine inhibition of neutrophil apoptosis leads to reduced levels of H3T45ph. We identify protein kinase C-delta as the kinase responsible for H3T45ph in vitro and in vivo. Given the nucleosomal position of H3T45, we postulate that H3T45ph induces structural change within the nucleosome to facilitate DNA nicking and/or fragmentation.
From the Wellcome Trust and Cancer Research UK Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, United Kingdom.
Paul J
PJ
Hurd
From the Wellcome Trust and Cancer Research UK Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, United Kingdom.
Andrew J
AJ
Bannister
From the Wellcome Trust and Cancer Research UK Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, United Kingdom.
Karen
K
Halls
From the Wellcome Trust and Cancer Research UK Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, United Kingdom; Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 OXY, United Kingdom.
Mark A
MA
Dawson
Max Planck Institute of Biochemistry, Department of Proteomics and Signal Transduction, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Michiel
M
Vermeulen
Max Planck Institute of Biochemistry, Department of Proteomics and Signal Transduction, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Jesper V
JV
Olsen
Department of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Heba
H
Ismail
Division of Gene Regulation and Expression, The Wellcome Trust Biocentre, Department of Biochemistry, University of Dundee, Dundee DD1 5EH, United Kingdom.
Joanna
J
Somers
Max Planck Institute of Biochemistry, Department of Proteomics and Signal Transduction, Am Klopferspitz 18, D-82152 Martinsried, Germany.
Matthias
M
Mann
Division of Gene Regulation and Expression, The Wellcome Trust Biocentre, Department of Biochemistry, University of Dundee, Dundee DD1 5EH, United Kingdom.
Tom
T
Owen-Hughes
Department of Structural and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
Ivan
I
Gout
From the Wellcome Trust and Cancer Research UK Gurdon Institute and Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, United Kingdom. Electronic address: tk106@mole.bio.cam.ac.uk.
Tony
T
Kouzarides
D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D018922:HL-60 Cells; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009504:Neutrophils / Q000166:cytology* / Q000378:metabolism*; D009707:Nucleosomes / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011487:Protein Conformation; D051745:Protein Kinase C-delta / Q000378:metabolism; D013912:Threonine / Q000378:metabolism
D006657:Histones; D009707:Nucleosomes; D013912:Threonine; D051745:Protein Kinase C-delta