title: Fumarylacetoacetate inhibits the initial step of the base excision repair pathway: implication for the pathogenesis of tyrosinemia type I.
abstract: Hereditary tyrosinemia type I (HT1) is an autosomal recessive disease caused by a deficiency in human fumarylacetoacetate (FAA) hydrolase (FAH), which is the last enzyme in the catabolic pathway of tyrosine. Several reports suggest that intracellular accumulation of intermediates of tyrosine catabolism, such as FAA and succinylacetone (SA) is important for the pathogenesis in liver and kidney of HT1 patients. In this work, we examined the effect of FAA and SA on DNA glycosylases initiating base excision repair (BER), which is the most important pathway for removing mutagenic DNA base lesions. In vitro assays monitoring DNA glycosylase activities demonstrated that FAA but not SA inhibited base removal. In particular, the Neil1 and Neil2 DNA glycosylases were strongly inhibited, whereas inhibition of Nth1 and Ogg1 were less efficient. These DNA glycosylases initiate excision of a broad range of mutagenic oxidative base lesions. Further, FAA showed a modest inhibitory effect on the activity of the alkylbase DNA glycosylase Aag and no significant inhibition of the uracil DNA glycosylase Ung2. These data indicate that FAA inhibition of DNA glycosylases removing oxidative base lesions in HT1 patients may increase mutagenesis, suggesting an important mechanism for development of hepatocarcinoma and somatic mosaicism.
authors.affiliation: Department of Medical Biochemistry, University of Oslo and Oslo University Hospital, Oslo, Norway.
authors.forename: Yngve T
authors.initials: YT
authors.lastname: Bliksrud
authors.forename: Amund
authors.initials: A
authors.lastname: Ellingsen
authors.forename: Magnar
authors.initials: M
authors.lastname: Bjørås
mesh_terms: D000090:Acetoacetates / Q000494:pharmacology*; D004247:DNA / Q000235:genetics; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism; D043224:Deoxyribonuclease (Pyrimidine Dimer) / Q000235:genetics / Q000378:metabolism; D006537:Heptanoates / Q000494:pharmacology; D006801:Humans; D016296:Mutagenesis / Q000235:genetics; D020176:Tyrosinemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000090:Acetoacetates; D006537:Heptanoates; C105171:fumarylacetoacetate; C020804:succinylacetone; D004247:DNA; D043224:Deoxyribonuclease (Pyrimidine Dimer); C468347:NTHL1 protein, human; C492570:CCNO protein, human; D045647:DNA Glycosylases; C473634:NEIL1 protein, human; C479058:oxoguanine glycosylase 1, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C473642:NEIL2 protein, human