title: Automodification switches PARP-1 function from chromatin architectural protein to histone chaperone.
abstract: Poly [ADP-ribose] polymerase 1 (PARP-1) is a highly abundant chromatin-associated enzyme. It catalyzes the NAD(+)-dependent polymerization of long chains of poly-ADP ribose (PAR) onto itself in response to DNA damage and other cues. More recently, the enzymatic activity of PARP-1 has also been implicated in the regulation of gene expression. The molecular basis for the functional switch from chromatin architectural protein to transcription factor and DNA damage responder, triggered by PARP-1 automodification, is unknown. Here, we show that unmodified PARP-1 engages in at least two high-affinity binding modes with chromatin, one of which does not involve free DNA ends, consistent with its role as a chromatin architectural protein. Automodification reduces PARP-1 affinity for intact chromatin but not for nucleosomes with exposed DNA ends. Automodified (AM) PARP-1 has the ability to sequester histones (both in vitro and in cells) and to assemble nucleosomes efficiently in vitro. This unanticipated nucleosome assembly activity of AM-PARP-1, coupled with the fast turnover of the modification, suggests a model in which DNA damage or transcription events trigger transient histone chaperone activity.
authors.affiliation: Department of Biochemistry and Molecular Biology, and.
authors.forename: Uma M
authors.initials: UM
authors.lastname: Muthurajan
authors.affiliation: Department of Biochemistry and Molecular Biology, and.
authors.forename: Maggie R D
authors.initials: MR
authors.lastname: Hepler
authors.affiliation: Department of Biochemistry and Molecular Biology, and Howard Hughes Medical Institute, Colorado State University, Fort Collins, CO 80523-1870.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Hieb
authors.affiliation: Department of Biochemistry and Molecular Biology, and.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Clark
authors.affiliation: Department of Biochemistry and Molecular Biology, and.
authors.forename: Michael
authors.initials: M
authors.lastname: Kramer
authors.affiliation: Department of Biochemistry and Molecular Biology, and.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yao
authors.affiliation: Department of Biochemistry and Molecular Biology, and Howard Hughes Medical Institute, Colorado State University, Fort Collins, CO 80523-1870 kluger@lamar.colostate.edu.
authors.forename: Karolin
authors.initials: K
authors.lastname: Luger
mesh_terms: D002843:Chromatin / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology; D031541:Fluorescence Resonance Energy Transfer; D056488:Histone Chaperones / Q000378:metabolism*; D006801:Humans; D009707:Nucleosomes / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D002843:Chromatin; D056488:Histone Chaperones; D009707:Nucleosomes; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: HI-FI FRET; dissociation constant; linker DNA; posttranslational modification