Oxidative DNA damage repair in mammalian cells: A new perspective

Tapas K. Hazra, Aditi Das, Soumita Das, Sujata Choudhury, Yoke W. Kow, Rabindra Roy

Research output: Contribution to journalArticle

210 Scopus citations

Abstract

Oxidatively induced DNA lesions have been implicated in the etiology of many diseases (including cancer) and in aging. Repair of oxidatively damaged bases in all organisms occurs primarily via the DNA base excision repair (BER) pathway, initiated with their excision by DNA glycosylases. Only two mammalian DNA glycosylases, OGG1 and NTH1 of E. coli Nth family, were previously characterized, which excise majority of the oxidatively damaged base lesions. We recently discovered and characterized two human orthologs of E. coli Nei, the prototype of the second family of oxidized base-specific glycosylases and named them NEIL (Nei-like)-1 and 2. NEILs are distinct from NTH1 and OGG1 in structural features and reaction mechanism but act on many of the same substrates. Nth-type DNA glycosylases after base excision, cleave the DNA strand at the resulting AP-site to produce a 3′-αβ unsaturated aldehyde whereas Nei-type enzymes produce 3′-phosphate terminus. E. coli APEs efficiently remove both types of termini in addition to cleaving AP sites to generate 3′-OH, the primer terminus for subsequent DNA repair synthesis. In contrast, the mammalian APE, APE1, which has an essential role in NTH1/OGG1-initiated BER, has negligible 3′-phosphatase activity and is dispensable for NEIL-initiated BER. Polynucleotide kinase (PNK), present in mammalian cells but not in E. coli, removes the 3′ phosphate, and is involved in NEIL-initiated BER. NEILs show a unique preference for excising lesions from a DNA bubble, while most DNA glycosylases, including OGG1 and NTH1, are active only with duplex DNA. The dichotomy in the preference of NEILs and NTH1/OGG1 for bubble versus duplex DNA substrates suggests that NEILs function preferentially in repair of base lesions during replication and/or transcription and hence play a unique role in maintaining the functional integrity of mammalian genomes.

Original languageEnglish (US)
Pages (from-to)470-480
Number of pages11
JournalDNA Repair
Volume6
Issue number4
DOIs
StatePublished - Apr 1 2007

Keywords

  • Base excision repair
  • Oxidative DNA damage
  • PNK-dependent BER
  • Reactive oxygen species

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Oxidative DNA damage repair in mammalian cells: A new perspective'. Together they form a unique fingerprint.

  • Cite this