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Titolo:
A MAMMALIAN DNA-REPAIR ENZYME THAT EXCISES OXIDATIVELY DAMAGED GUANINES MAPS TO A LOCUS FREQUENTLY LOST IN LUNG-CANCER
Autore:
LU RZ; NASH HM; VERDINE GL;
Indirizzi:
HARVARD UNIV,DEPT CHEM & CHEM BIOL CAMBRIDGE MA 02138 HARVARD UNIV,DEPT CHEM & CHEM BIOL CAMBRIDGE MA 02138
Titolo Testata:
Current biology
fascicolo: 6, volume: 7, anno: 1997,
pagine: 397 - 407
SICI:
0960-9822(1997)7:6<397:AMDETE>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
SMALL-CELL CARCINOMA; ESCHERICHIA-COLI; 8-HYDROXYGUANINE 7,8-DIHYDRO-8-OXOGUANINE; INSITU HYBRIDIZATION; MUTAGENIC SUBSTRATE; CATALYTIC MECHANISM; ENDONUCLEASE-III; FPG PROTEIN; SHORT ARM; MUTATIONS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
60
Recensione:
Indirizzi per estratti:
Citazione:
R.Z. Lu et al., "A MAMMALIAN DNA-REPAIR ENZYME THAT EXCISES OXIDATIVELY DAMAGED GUANINES MAPS TO A LOCUS FREQUENTLY LOST IN LUNG-CANCER", Current biology, 7(6), 1997, pp. 397-407

Abstract

Background: Guanine residues in the genome are vulnerable to attack by free radicals and reactive oxygen species. A major lesion thus produced, 8-oxoguanine ((O)G), causes mutations by mis-pairing with adenineduring replication. In bacteria and budding yeast, (O)G is removed from the genome through the action of base-excision DNA repair (BER) enzymes, which catalyze expulsion of the aberrant base and excision of its sugar moiety from the DNA backbone. Although (O)G is known to be produced in and cleansed from mammalian genomes, the enzymes responsible for (O)G repair in these cells have remained elusive. Results: Here, we report the cloning and biochemical characterization of mammalian BERenzymes that specifically target (O)G residues in DNA. These 8-oxoguanine DNA glycosylases, hOgg1 (human) and mOgg1 (murine), are homologous to each other and to yeast Ogg1. They also contain an active site motif - the Helix-hairpin-Helix, Gly/Pro-rich-Asp motif - characteristicof a superfamily of BER proteins with a similar core fold and active site geometry. Both hOgg1 and mOgg1 exhibit exquisite selectivity for the base opposite (O)G in DNA, operating with high efficiency only on (O)G base-paired to cytosine. Furthermore, hOgg1 and mOgg1 are unable to process a panel of alternative lesions, including 8-oxoadenine, yetbind with high affinity to synthetic abasic site analogs. The proteins operate through a classical glycosylase/lyase catalytic mechanism; mutation of a catalytically essential lysine residue results in loss ofcatalytic potency but retention of binding to (O)G-containing oligonucleotides. The hOGG1 gene is localized on the short arm of chromosome 3 (3p25/26) in a region commonly deleted in cancers. Conclusions: These results conclusively establish the existence and identity of an 8-oxoguanine DNA glycosylase/lyase in human and murine cells, completing the triad of proteins that together protect mammals from the genotoxic effects of guanine oxidation. The observation that at least one alleleof hOGG1 is commonly deleted in cancer cells suggests that such cellsmay possess a reduced capacity to counter the mutagenic effects of reactive oxygen species, a deficiency that could increase their overall genomic instability. This speculation is fueled by recent observationsthat cells constitutively active for the Ras/Raf pathway constitutively produce high levels of superoxide, a known generator of (O)G.

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Documento generato il 15/07/20 alle ore 08:21:32