title: 2,3,7,8-Tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TiPARP, ARTD14) is a mono-ADP-ribosyltransferase and repressor of aryl hydrocarbon receptor transactivation.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiPARP/ARTD14) is a member of the PARP family and is regulated by the aryl hydrocarbon receptor (AHR); however, little is known about TiPARP function. In this study, we examined the catalytic function of TiPARP and determined its role in AHR transactivation. We observed that TiPARP exhibited auto-mono-ADP-ribosyltransferase activity and ribosylated core histones. RNAi-mediated knockdown of TiPARP in T-47D breast cancer and HuH-7 hepatoma cells increased TCDD-dependent cytochrome P450 1A1 (CYP1A1) and CYP1B1 messenger RNA (mRNA) expression levels and recruitment of AHR to both genes. Overexpression of TiPARP reduced AHR-dependent increases in CYP1A1-reporter gene activity, which was restored by overexpression of AHR, but not aryl hydrocarbon receptor nuclear translocator. Deletion and mutagenesis studies showed that TiPARP-mediated inhibition of AHR required the zinc-finger and catalytic domains. TiPARP and AHR co-localized in the nucleus, directly interacted and both were recruited to CYP1A1 in response to TCDD. Overexpression of Tiparp enhanced, whereas RNAi-mediated knockdown of TiPARP reduced TCDD-dependent AHR proteolytic degradation. TCDD-dependent induction of AHR target genes was enhanced in Tiparp(-/-) mouse embryonic fibroblasts compared with wildtype controls. Our findings show that TiPARP is a mono-ADP-ribosyltransferase and a transcriptional repressor of AHR, revealing a novel negative feedback loop in AHR signalling.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S1A8, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: MacPherson
authors.forename: Laura
authors.initials: L
authors.lastname: Tamblyn
authors.forename: Sharanya
authors.initials: S
authors.lastname: Rajendra
authors.forename: Fernando
authors.initials: F
authors.lastname: Bralha
authors.forename: J Peter
authors.initials: JP
authors.lastname: McPherson
authors.forename: Jason
authors.initials: J
authors.lastname: Matthews
mesh_terms: D036002:ADP Ribose Transferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D033703:Nucleoside Transport Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000378:metabolism*; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation; D016335:Zinc Fingers
chemical_list: D033703:Nucleoside Transport Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D012097:Repressor Proteins; C579717:TiPARP protein, human; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D036002:ADP Ribose Transferases; D011065:Poly(ADP-ribose) Polymerases