Choreography of oxidative damage repair in mammalian genomes.
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.
Mitra
Sankar
S
Sealy Center for Molecular Science and Department of Human Biological Chemistry, University of Texas Medical Branch, Galveston, TX 77555, USA. samitra@utmb.edu
Izumi
Tadahide
T
Boldogh
Istvan
I
Bhakat
Kishor K
KK
Hill
Jeff W
JW
Hazra
Tapas K
TK
D000818:Animals; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D005057:Eukaryotic Cells / Q000502:physiology*; D016678:Genome; D006801:Humans; D009699:N-Glycosyl Hydrolases / Q000502:physiology*; D018384:Oxidative Stress / Q000235:genetics*; D017382:Reactive Oxygen Species; D015398:Signal Transduction
D002843:Chromatin; D017382:Reactive Oxygen Species; D009699:N-Glycosyl Hydrolases