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Titolo:
Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage
Autore:
Klungland, A; Rosewell, I; Hollenbach, S; Larsen, E; Daly, G; Epe, B; Seeberg, E; Lindahl, T; Barnes, DE;
Indirizzi:
Imperial Canc Res Fund, Clare Hall Labs, S Mimms EN6 3LD, Herts, England Imperial Canc Res Fund S Mimms Herts England EN6 3LD 3LD, Herts, England Univ Oslo, Inst Med Microbiol, Dept Biol Mol, Natl Hosp, N-0027 Oslo, Norway Univ Oslo Oslo Norway N-0027 pt Biol Mol, Natl Hosp, N-0027 Oslo, Norway Univ Mainz, Inst Pharm, D-55099 Mainz, Germany Univ Mainz Mainz Germany D-55099 inz, Inst Pharm, D-55099 Mainz, Germany
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 23, volume: 96, anno: 1999,
pagine: 13300 - 13305
SICI:
0027-8424(19991109)96:23<13300:AOPDLI>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
EXCISION-REPAIR; HUMAN HOMOLOG; OGG1 GENE; 8-HYDROXYGUANINE 7,8-DIHYDRO-8-OXOGUANINE; SPONTANEOUS MUTATION; TRANSGENIC MICE; DEFICIENT MICE; GLYCOSYLASE; 8-OXOGUANINE; CLONING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
45
Recensione:
Indirizzi per estratti:
Indirizzo: Lindahl, T Imperial Canc Res Fund, Clare Hall Labs, S Mimms EN6 3LD, Herts, England Imperial Canc Res Fund S Mimms Herts England EN6 3LD , England
Citazione:
A. Klungland et al., "Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage", P NAS US, 96(23), 1999, pp. 13300-13305

Abstract

DNA damage generated by oxidant byproducts of cellular metabolism has beenproposed as a key factor in cancer and aging. Oxygen free radicals cause predominantly base damage in DNA, and the most frequent mutagenic base lesion is 7.8-dihydro-8-oxoguanine (8-oxoG). This altered base can pair with A as well as C residues, leading to a greatly increased frequency of spontaneous C.C --> T.A transversion mutations in repair-deficient bacterial and yeast cells. Eukaryotic cells use a specific DNA glycosylase. the product of the OGG1 gene, to excise 8-oxoG from DNA. To assess the role of the mammalian enzyme in repair of DNA damage and prevention of carcinogenesis, we have generated homozygous ogg1(-/-) null mice. These animals are viable but accumulate abnormal levels of 8-oxoG in their genomes, Despite this increase inpotentially miscoding DNA lesions, OGG1-deficient mice exhibit only a moderately, but significantly, elevated spontaneous mutation rate in nonproliferative tissues, do not develop malignancies, and show no marked pathological changes. Extracts of ogg1 null mouse tissues cannot excise the damaged base, but there is significant slow removal in vivo from proliferating cells. These findings suggest that in the absence of the DNA glycosylase, and in apparent contrast to bacterial and yeast cells, an alternative repair pathway functions to minimize the effects of an increased load of 8-oxoG in the genome and maintain a low endogenous mutation frequency.

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Documento generato il 14/07/20 alle ore 19:51:35