title: Mechanism of early biphasic activation of poly(ADP-ribose) polymerase-1 in response to ultraviolet B radiation.
abstract: The damage to DNA caused by ultraviolet B radiation (280-320 nm) contributes significantly to development of sunlight-induced skin cancers. The susceptibility of mice to ultraviolet B-induced skin carcinogenesis is increased by an inhibitor of the DNA damage-activated nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP), hence PARP activation is likely to be associated with cellular responses that suppress carcinogenesis. To understand the role of activated PARP in these cellular functions, we need to first clearly identify the cause of PARP activation in ultraviolet B-irradiated cells. Ultraviolet B, like ultraviolet C, causes direct DNA damage of cyclobutane pyrimidine dimer and 6, 4-photoproduct types, which are subjected to the nucleotide excision repair. Moreover, ultraviolet B also causes oxidative DNA damage, which is subjected to base excision repair. To identify which of these two types of DNA damage activates PARP, we examined mechanism of early PARP activation in mouse fibroblasts exposed to ultraviolet B and C radiations. The ultraviolet B-irradiated cells rapidly activated PARP in two distinct phases, initially within the first 5 minutes and later between 60-120 minutes, whereas ultraviolet C-irradiated cells showed only the immediate PARP activation. Using antioxidants, local irradiation, chromatin immunoprecipitation and in vitro PARP assays, we identified that ultraviolet radiation-induced direct DNA damage, such as thymine dimers, cause the initial PARP activation, whereas ultraviolet B-induced oxidative damage cause the second PARP activation. Our results suggest that cells can selectively activate PARP for participation in different cellular responses associated with different DNA lesions.
authors.affiliation: Laboratory for Skin Cancer Research, CHUL Research Center (CHUQ), Faculty of Medicine, Laval University, 2705, Laurier Boulevard, Québec, QC, G1V 4G2, Canada.
authors.forename: Momchil D
authors.initials: MD
authors.lastname: Vodenicharov
authors.forename: Medini M
authors.initials: MM
authors.lastname: Ghodgaonkar
authors.forename: Sabina S
authors.initials: SS
authors.lastname: Halappanavar
authors.forename: Rashmi G
authors.initials: RG
authors.lastname: Shah
authors.forename: Girish M
authors.initials: GM
authors.lastname: Shah
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology; D004789:Enzyme Activation / Q000528:radiation effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects; D007700:Kinetics; D051379:Mice; D016877:Oxidants / Q000378:metabolism / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000528:radiation effects; D011740:Pyrimidine Dimers / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000975:Antioxidants; D016877:Oxidants; D011740:Pyrimidine Dimers; D011064:Poly Adenosine Diphosphate Ribose; D004247:DNA; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases