title: Phosphorylation-mediated control of histone chaperone ASF1 levels by Tousled-like kinases.
abstract: Histone chaperones are at the hub of a diverse interaction networks integrating a plethora of chromatin modifying activities. Histone H3/H4 chaperone ASF1 is a target for cell-cycle regulated Tousled-like kinases (TLKs) and both proteins cooperate during chromatin replication. However, the precise role of post-translational modification of ASF1 remained unclear. Here, we identify the TLK phosphorylation sites for both Drosophila and human ASF1 proteins. Loss of TLK-mediated phosphorylation triggers hASF1a and dASF1 degradation by proteasome-dependent and independent mechanisms respectively. Consistent with this notion, introduction of phosphorylation-mimicking mutants inhibits hASF1a and dASF1 degradation. Human hASF1b is also targeted for proteasome-dependent degradation, but its stability is not affected by phosphorylation indicating that other mechanisms are likely to be involved in control of hASF1b levels. Together, these results suggest that ASF1 cellular levels are tightly controlled by distinct pathways and provide a molecular mechanism for post-translational regulation of dASF1 and hASF1a by TLK kinases.
authors.affiliation: Department of Zoology and National Research Center Frontiers in Genetics, University of Geneva, Geneva, Switzerland.
authors.forename: Maxim
authors.initials: M
authors.lastname: Pilyugin
authors.forename: Jeroen
authors.initials: J
authors.lastname: Demmers
authors.forename: C Peter
authors.initials: CP
authors.lastname: Verrijzer
authors.forename: Francois
authors.initials: F
authors.lastname: Karch
authors.forename: Yuri M
authors.initials: YM
authors.lastname: Moshkin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology; D006657:Histones / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D055550:Protein Stability
chemical_list: C491641:ASF1A protein, human; C491640:ASF1B protein, human; D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D006657:Histones; D018832:Molecular Chaperones; C491642:asf1 protein, Drosophila; C498930:tlk protein, Drosophila; D017346:Protein Serine-Threonine Kinases; C425323:TLK1 protein, human; D046988:Proteasome Endopeptidase Complex