title: Poly(ADP-ribose) polymerase 1 is inhibited by a histone H2A variant, MacroH2A, and contributes to silencing of the inactive X chromosome.
abstract: Poly(ADP-ribose) polymerase 1 (PARP-1) is a nuclear enzyme that is involved in modulating chromatin structure, regulation of gene expression, and sensing DNA damage. Here, we report that PARP-1 enzymatic activity is inhibited by macroH2A, a vertebrate histone H2A variant that is enriched on facultative heterochromatin. MacroH2A family members have a large C-terminal non-histone domain (NHD) and H2A-like histone domain. MacroH2A1.2 and PARP-1 interact in vivo and in vitro via the NHD. The NHD of each macroH2A family member was sufficient to inhibit PARP-1 enzymatic activity in vitro. The NHD of macroH2A1.2 was a mixed inhibitor of PARP-1 catalytic activity, with affects on both catalytic activity and the substrate binding affinity of PARP-1. Depletion of PARP-1 by RNA interference caused reactivation of a reporter gene on the inactive X chromosome, demonstrating that PARP-1 participates in the maintenance of silencing. These results suggest that one function of macroH2A in gene silencing is to inhibit PARP-1 enzymatic activity, and this may affect PARP-1 association with chromatin.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.
authors.forename: Dmitri A
authors.initials: DA
authors.lastname: Nusinow
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Hernández-Muñoz
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Fazzio
authors.forename: Girish M
authors.initials: GM
authors.lastname: Shah
authors.forename: W Lee
authors.initials: WL
authors.lastname: Kraus
authors.forename: Barbara
authors.initials: B
authors.lastname: Panning
mesh_terms: D002460:Cell Line; D002843:Chromatin / Q000201:enzymology* / Q000235:genetics; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D049951:X Chromosome Inactivation / Q000502:physiology*
chemical_list: D002843:Chromatin; D006657:Histones; C120756:macroH2A histone; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases