Journal of Inherited Metabolic Disease

, Volume 36, Issue 5, pp 773–778 | Cite as

Fumarylacetoacetate inhibits the initial step of the base excision repair pathway: implication for the pathogenesis of tyrosinemia type I

  • Yngve T. Bliksrud
  • Amund Ellingsen
  • Magnar Bjørås
Original Article


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.


Base Excision Repair Abasic Site Base Lesion Somatic Mosaicism Succinylacetone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Lars Mørkrid for help with statistical analyses and Pernille Strøm Andersen and Mari Ytre-Arne for technical assistance with protein purification. We thank Professor Cynthia Burrows for the Sp oligo.

Conflict of interest



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Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2012

Authors and Affiliations

  • Yngve T. Bliksrud
    • 1
  • Amund Ellingsen
    • 1
    • 2
    • 3
  • Magnar Bjørås
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of Medical BiochemistryUniversity of Oslo and Oslo University HospitalOsloNorway
  2. 2.Department of MicrobiologyUniversity of Oslo and Oslo University HospitalOsloNorway
  3. 3.Centre of Molecular Biology and NeuroscienceUniversity of Oslo and Oslo University HospitalOsloNorway
  4. 4.A3.3012, Oslo University Hospital HFOsloNorway

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