Choreography of oxidative damage repair in mammalian genomes

Sankar Mitra, Tadahide Izumi, Istvan Boldogh, Kishor K. Bhakat, Jeff W. Hill, Tapas K. Hazra

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

The lesions induced by reactive oxygen species in both nuclear and mitochondrial genomes include altered bases, abasic (AP) sites, and single-strand breaks, all repaired primarily via the base excision repair (BER) pathway. Although the basic BER process (consisting of five sequential steps) could be reconstituted in vitro with only four enzymes, it is now evident that repair of oxidative damage, at least in mammalian cell nuclei, is more complex, and involves a number of additional proteins, including transcription- and replication-associated factors. These proteins may be required in sequential repair steps in concert with other cellular changes, starting with nuclear targeting of the early repair enzymes in response to oxidative stress, facilitation of lesion recognition, and access by chromatin unfolding via histone acetylation, and formation of metastable complexes of repair enzymes and other accessory proteins. Distinct, specific subclasses of protein complexes may be formed for repair of oxidative lesions in the nucleus in transcribed vs. nontranscribed sequences in chromatin, in quiescent vs. cycling cells, and in nascent vs. parental DNA strands in replicating cells. Characterizing the proteins for each repair subpathway, their signaling-dependent modifications and interactions in the nuclear as well as mitochondrial repair complexes, will be a major focus of future research in oxidative damage repair.

Original languageEnglish
Pages (from-to)15-28
Number of pages14
JournalFree Radical Biology and Medicine
Volume33
Issue number1
DOIs
StatePublished - Jul 1 2002

Bibliographical note

Funding Information:
This work has been supported by NIH grants CA53791, CA81063, ES08457, AG10514 (S.M.), CA84461 (I.B.), and NIEHS Center Grant ES06676. We thank Drs. A. Kurosky and T. Wood, Directors of Protein Chemistry and Molecular Biology Core, respectively, of NIEHS Center for essential materials and service as well as technical help. We also thank Dr. Priscilla Cooper for sharing unpublished results.

Keywords

  • Base excision repair
  • Chromatin unfolding
  • Coordination of repair reactions
  • DNA damage
  • Free radicals
  • Organelle targeting

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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