title: Double-stranded DNA binding domain of poly(ADP-ribose) polymerase-1 and molecular insight into the regulation of its activity.
abstract: Poly(ADP-ribose) polymerase-1 (PARP-1) modifies various proteins, including itself, with ADP-ribose polymers (automodification). Polymer synthesis is triggered by binding of its zinc finger 1 (Zn1) and 2 (Zn2) to DNA breaks and is followed by inactivation through automodification. The multiple functional domains of PARP-1 appear to regulate activation and automodification-mediated inactivation of PARP-1. However, the roles of these domains in activation-inactivation processes are not well understood. Our results suggest that Zn1, Zn2, and a domain identified in this study, the double-stranded DNA binding (DsDB) domain, are involved in DNA break-dependent activation of PARP-1. We found that binding of the DsDB domain to double-stranded DNA and DNA break recognition by Zn1 and Zn2, whose actual binding targets are likely to be single-stranded DNA, lead to the activation of PARP-1. In turn, the displacement of single- and double-stranded DNA from Zn2 and the DsDB domain caused by ADP-ribose polymer synthesis results in the dissociation of PARP-1 from DNA breaks and thus its inactivation. We also found that the WGR domain is one of the domains involved in the RNA-dependent activation of PARP-1. Furthermore, because zinc finger 3 (Zn3) has the ability to bind to single-stranded RNA, it may have an indirect role in RNA-dependent activation. PARP-1 functional domains, which are involved in oligonucleic acid binding, therefore coordinately regulate PARP-1 activity depending on the status of the neighboring oligonucleic acids. Based on these results, we proposed a model for the regulation of PARP-1 activity.
authors.affiliation: Laboratory of DNA Damage Responses and Bioimaging, Faculty of Medicine, Laval University Medical Centre (CHUQ), Laval University, Québec, Québec G1V 4G2, Canada.
authors.forename: Orlando
authors.initials: O
authors.lastname: Huambachano
authors.forename: Fatima
authors.initials: F
authors.lastname: Herrera
authors.forename: Ann
authors.initials: A
authors.lastname: Rancourt
authors.forename: Masahiko S
authors.initials: MS
authors.lastname: Satoh
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D004247:DNA / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000502:physiology*; D004277:DNA, Single-Stranded / Q000378:metabolism*; D006801:Humans; D008956:Models, Chemical; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012313:RNA / Q000378:metabolism; D013329:Structure-Activity Relationship; D016335:Zinc Fingers / Q000502:physiology
chemical_list: D004277:DNA, Single-Stranded; D010446:Peptide Fragments; D000246:Adenosine Diphosphate Ribose; D012313:RNA; D004247:DNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases