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PMID: 19179336 Published · ppublish English Journal Article Research Support, N.I.H., Intramural

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

The Journal of biological chemistry ·Vol. 284 ·No. 14 ·2009-04-03 ·Pages 9270-9

Muftuoglu M, de Souza-Pinto NC, Dogan A, Aamann M, Stevnsner T, Rybanska I, Kirkali G, Dizdaroglu M, Bohr VA

Abstract

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.

MeSH Terms
Adenosine Triphosphatases/metabolism Animals DNA/genetics,metabolism DNA Glycosylases/genetics,metabolism DNA Helicases/genetics,metabolism DNA Repair/genetics DNA Repair Enzymes/deficiency,genetics,metabolism DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism HeLa Cells Humans Mice Mice, Knockout Poly-ADP-Ribose Binding Proteins Protein Binding Pyrimidines/metabolism Substrate Specificity
Chemicals
Poly-ADP-Ribose Binding Proteins Pyrimidines 4,6-diamino-5-N-formamidopyrimidine DNA DNA Glycosylases NEIL1 protein, human Adenosine Triphosphatases DNA Helicases ERCC6 protein, human Ercc6 protein, mouse DNA-(Apurinic or Apyrimidinic Site) Lyase DNA Repair Enzymes
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Muftuoglu Meltem
Laboratory of Molecular Gerontology, NIA Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.
de Souza-Pinto Nadja C
Dogan Arin
Aamann Maria
Stevnsner Tinna
Rybanska Ivana
Kirkali Güldal
Dizdaroglu Miral
Bohr Vilhelm A
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Article Info
Journal
The Journal of biological chemistry
Abbr.
J Biol Chem
ISSN
0021-9258
DOI
10.1074/jbc.M807006200
Published
2009-04-03
Epub
2009-00-29
Pages
9270-9
Language
English
Region
United States
NLM ID
2985121R
PMCID
PMC2666579
Subset
IM
Grants
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1074/jbc.M807006200 PMC Full Text View journal details
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