Phosphorylation of histone H3 Ser10 establishes a hierarchy for subsequent intramolecular modification events.
Phosphorylation of Ser10 of histone H3 regulates chromosome condensation and transcriptional activity. Using time-resolved, high-resolution NMR spectroscopy, we demonstrate that histone H3 Ser10 phosphorylation inhibits checkpoint kinase 1 (Chk1)- and protein kinase C (PKC)-mediated modification of Thr11 and Thr6, the respective primary substrate sites of these kinases. On unmodified H3, both enzymes also target Ser10 and thereby establish autoinhibitory feedback states on individual H3 tails. Whereas phosphorylated Ser10 does not affect acetylation of Lys14 by Gcn5, phosphorylated Thr11 impedes acetylation. Our observations reveal mechanistic hierarchies of H3 phosphorylation and acetylation events and provide a framework for intramolecular modification cross-talk within the N terminus of histone H3.
Department of NMR-supported Structural Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Berlin, Germany.
Stamatios
S
Liokatis
Alexandra
A
Stützer
Simon J
SJ
Elsässer
Francois-Xavier
FX
Theillet
Rebecca
R
Klingberg
Barth
B
van Rossum
Dirk
D
Schwarzer
C David
CD
Allis
Wolfgang
W
Fischle
Philipp
P
Selenko
D000107:Acetylation; D000818:Animals; D064127:Aurora Kinases; D001483:Base Sequence; D001665:Binding Sites; D000071877:Checkpoint Kinase 1; D017931:DNA Primers / Q000235:genetics; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008958:Models, Molecular; D009707:Nucleosomes / Q000378:metabolism; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D013912:Threonine / Q000737:chemistry; D029867:Xenopus Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
D017931:DNA Primers; D006657:Histones; D009707:Nucleosomes; D011994:Recombinant Proteins; D029867:Xenopus Proteins; D013912:Threonine; D012694:Serine; D011494:Protein Kinases; D064127:Aurora Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605875:Chek1 protein, Xenopus; D017346:Protein Serine-Threonine Kinases; D051571:Protein Kinase C-alpha; D008239:Lysine