title: VprBP has intrinsic kinase activity targeting histone H2A and represses gene transcription.
abstract: Histone modifications play important roles in the regulation of gene expression and chromatin organization. VprBP has been implicated in transcriptionally silent chromatin formation and cell-cycle regulation, but the molecular basis underlying such effects remains unclear. Here we report that VprBP possesses an intrinsic protein kinase activity and is capable of phosphorylating histone H2A on threonine 120 (H2AT120p) in a nucleosomal context. VprBP is localized to a large set of tumor suppressor genes and blocks their transcription, in a manner that is dependent on its kinase activity toward H2AT120. The functional significance of VprBP-mediated H2AT120p is further underscored by the fact that RNAi knockdown and small-molecule inhibition of VprBP reactivate growth regulatory genes and impede tumor growth. Our findings establish VprBP as a major kinase responsible for H2AT120p in cancer cells and suggest that VprBP inhibition could be a new strategy for the development of anticancer therapeutics.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA; Norris Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90089, USA.
authors.forename: Kyunghwan
authors.initials: K
authors.lastname: Kim
authors.forename: Jin-Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Joong-Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Jongkyu
authors.initials: J
authors.lastname: Choi
authors.forename: Yong Suk
authors.initials: YS
authors.lastname: Lee
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Kyu
authors.initials: K
authors.lastname: Heo
authors.forename: Woojin
authors.initials: W
authors.lastname: An
mesh_terms: D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D064593:Heterografts; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D009707:Nucleosomes / Q000235:genetics; D010766:Phosphorylation; D010770:Phosphotransferases; D017346:Protein Serine-Threonine Kinases; D034622:RNA Interference; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D006657:Histones; D009707:Nucleosomes; D044767:Ubiquitin-Protein Ligases; D010770:Phosphotransferases; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases