PMID- 10557315
OWN - NLM
STAT- MEDLINE
DCOM- 19991213
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 96
IP  - 23
DP  - 1999 Nov 9
TI  - Accumulation of premutagenic DNA lesions in mice defective in removal of
      oxidative base damage.
PG  - 13300-5
AB  - DNA damage generated by oxidant byproducts of cellular metabolism has been
      proposed 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 G.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 in potentially 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.
FAU - Klungland, A
AU  - Klungland A
AD  - Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms,
      Hertfordshire EN6 3LD, United Kingdom.
FAU - Rosewell, I
AU  - Rosewell I
FAU - Hollenbach, S
AU  - Hollenbach S
FAU - Larsen, E
AU  - Larsen E
FAU - Daly, G
AU  - Daly G
FAU - Epe, B
AU  - Epe B
FAU - Seeberg, E
AU  - Seeberg E
FAU - Lindahl, T
AU  - Lindahl T
FAU - Barnes, D E
AU  - Barnes DE
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Mutagens)
RN  - 12133JR80S (Guanosine)
RN  - 3868-31-3 (8-hydroxyguanosine)
RN  - EC 3.2.2.- (N-Glycosyl Hydrolases)
RN  - EC 3.2.2.23 (DNA-Formamidopyrimidine Glycosylase)
SB  - IM
MH  - Animals
MH  - Base Sequence
MH  - Cell Nucleus/drug effects/metabolism
MH  - Chromatography, High Pressure Liquid
MH  - *DNA Damage
MH  - DNA Repair
MH  - DNA-Formamidopyrimidine Glycosylase
MH  - Electrochemistry
MH  - Guanosine/*analogs & derivatives/toxicity
MH  - Liver/drug effects/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Mutagens/*toxicity
MH  - Mutation
MH  - N-Glycosyl Hydrolases/genetics
MH  - *Oxidative Stress
PMC - PMC23942
EDAT- 1999/11/11 00:00
MHDA- 1999/11/11 00:01
CRDT- 1999/11/11 00:00
PHST- 1999/11/11 00:00 [pubmed]
PHST- 1999/11/11 00:01 [medline]
PHST- 1999/11/11 00:00 [entrez]
AID - 10.1073/pnas.96.23.13300 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13300-5. doi:
      10.1073/pnas.96.23.13300.