Mutator phenotype of mammalian cells due to deficiency of NEIL1 DNA glycosylase, an oxidized base-specific repair enzyme

Amit K. Maiti, Istvan Boldogh, Heidi Spratt, Sankar Mitra, Tapas Hazra

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The recently characterized NEIL1 and NEIL2 are distinct from the previously characterized mammalian DNA glycosylases (OGG1 and NTH1) involved in repair of oxidized bases because of the NEILs' preference for excising base lesions from single-stranded DNA present in bubble and fork structures. OGG1 and NTH1 are active only with duplex DNA. This raises the possibility that NEILs function in the repair of base lesions during DNA replication and/or transcription. S-phase-specific activation of only NEIL1 suggests its preferential involvement in repair during DNA replication. Here we show that antisense oligonucleotides specific for human or Chinese hamster NEIL1 decreased in vivo NEIL1 levels by 70-80%, concomitant with increased oxidative damage in the genome. Moreover, NEIL1 downregulation enhanced spontaneous mutation in the Hprt locus by about 3-fold in both Chinese hamster V79 and human bronchial A549 cell lines. The mutant frequency was further enhanced (7-8-fold) under oxidative stress. The majority of both spontaneous and induced mutations occurred at A·T base pairs, indicating that oxidized A and/or T are NEIL1's preferred in vivo substrates. NEIL1 thus plays a distinct and important role in repairing endogenous and induced mutagenic oxidized bases, and hence in maintaining the functional integrity of mammalian genomes.

Original languageEnglish (US)
Pages (from-to)1213-1220
Number of pages8
JournalDNA Repair
Volume7
Issue number8
DOIs
StatePublished - Aug 2 2008

Fingerprint

DNA Glycosylases
Cricetulus
DNA Replication
Repair
Cells
Genome
Phenotype
Mutation
Antisense Oligonucleotides
Single-Stranded DNA
DNA
Enzymes
Genes
S Phase
Base Pairing
Oxidative Stress
Oxidative stress
Down-Regulation
Transcription
Chemical activation

Keywords

  • BER
  • Hprt
  • Mutagenesis
  • NEIL1
  • Oxidative stress

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

Cite this

Mutator phenotype of mammalian cells due to deficiency of NEIL1 DNA glycosylase, an oxidized base-specific repair enzyme. / Maiti, Amit K.; Boldogh, Istvan; Spratt, Heidi; Mitra, Sankar; Hazra, Tapas.

In: DNA Repair, Vol. 7, No. 8, 02.08.2008, p. 1213-1220.

Research output: Contribution to journalArticle

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