Cockayne syndrome group B protein stimulates repair of formamidopyrimidines by NEIL1 DNA glycosylase

Research output: Contribution to journalJournal articleResearchpeer-review

Meltem Muftuoglu, Nadja C de Souza-Pinto, Arin Dogan, Maria Aamann, Tinna Stevnsner, Ivana Rybanska, Güldal Kirkali, Miral Dizdaroglu, Vilhelm A Bohr

Cockayne syndrome (CS) is a premature aging condition characterized by sensitivity to UV radiation. However, this phenotype does not explain the progressive neurodegeneration in CS patients. It could be due to the hypersensitivity of CSB-deficient cells to oxidative stress. So far most studies on the role of CSB in repair of oxidatively induced DNA lesions have focused on 7,8-dihydro-8-oxoguanine. This study examines the role of CSB in the repair of formamidopyrimidines 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) and 4,6-diamino-5-formamidopyrimidine (FapyAde), which are substrates for endonuclease VIII-like (NEIL1) DNA glycosylase. Results presented here show that csb(-/-) mice have a higher level of endogenous FapyAde and FapyGua in DNA from brain and kidney than wild type mice as well as higher levels of endogenous FapyAde in genomic DNA and mtDNA from liver. In addition, CSB stimulates NEIL1 incision activity in vitro, and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells. When CSB and NEIL1 are depleted from HeLa cells by short hairpin RNA knockdown, repair of induced FapyGua is strongly inhibited. These results suggest that CSB plays a role in repair of formamidopyrimidines, possibly by interacting with and stimulating NEIL1, and that accumulation of such modifications may have a causal role in the pathogenesis of CS.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume284
Issue number14
Pages (from-to)9270-9
Number of pages10
ISSN0021-9258
DOIs
Publication statusPublished - Apr 2009

    Research areas

  • Adenosine Triphosphatases, Animals, DNA, DNA Glycosylases, DNA Helicases, DNA Repair, DNA Repair Enzymes, DNA-(Apurinic or Apyrimidinic Site) Lyase, Hela Cells, Humans, Mice, Mice, Knockout, Protein Binding, Pyrimidines, Substrate Specificity

ID: 32446859