TY - JOUR
T1 - Choreography of oxidative damage repair in mammalian genomes
AU - Mitra, Sankar
AU - Izumi, Tadahide
AU - Boldogh, Istvan
AU - Bhakat, Kishor K.
AU - Hill, Jeff W.
AU - Hazra, Tapas K.
N1 - 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 Priscilla Cooper for sharing unpublished results.
PY - 2002/7/1
Y1 - 2002/7/1
N2 - 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.
AB - 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.
KW - Base excision repair
KW - Chromatin unfolding
KW - Coordination of repair reactions
KW - DNA damage
KW - Free radicals
KW - Organelle targeting
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U2 - 10.1016/S0891-5849(02)00819-5
DO - 10.1016/S0891-5849(02)00819-5
M3 - Article
C2 - 12086678
AN - SCOPUS:0036628725
SN - 0891-5849
VL - 33
SP - 15
EP - 28
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 1
ER -