title: PP1α, PP1β and Wip-1 regulate H4S47 phosphorylation and deposition of histone H3 variant H3.3.
abstract: Phosphorylation of histone H4 serine 47 (H4S47ph) is catalyzed by Pak2, a member of the p21-activated serine/threonine protein kinase (Pak) family and regulates the deposition of histone variant H3.3. However, the phosphatase(s) involved in the regulation of H4S47ph levels was unknown. Here, we show that three phosphatases (PP1α, PP1β and Wip1) regulate H4S47ph levels and H3.3 deposition. Depletion of each of the three phosphatases results in increased H4S47ph levels. Moreover, PP1α, PP1β and Wip1 bind H3-H4 in vitro and in vivo, whereas only PP1α and PP1β, but not Wip1, interact with Pak2 in vivo. These results suggest that PP1α, PP1β and Wip1 regulate the levels of H4S47ph through directly acting on H4S47ph, with PP1α and PP1β also likely regulating the activity of Pak2. Finally, depletion of PP1α, PP1β and Wip1 leads to increased H3.3 occupancy at candidate genes tested, elevated H3.3 deposition and enhanced association of H3.3 with its chaperones HIRA and Daxx. These results reveal a novel role of three phosphatases in chromatin dynamics in mammalian cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhiquan
authors.initials: Z
authors.lastname: Wang
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D056970:Co-Repressor Proteins; D006367:HeLa Cells; D056488:Histone Chaperones / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D012694:Serine / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; C086057:HIRA protein, human; D056488:Histone Chaperones; D006657:Histones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D014157:Transcription Factors; D012694:Serine; C515907:PAK2 protein, human; D054462:p21-Activated Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D000071636:Protein Phosphatase 2C