Carcinogenesis, Vol 19, 1299-1305, Copyright © 1998 by Oxford University Press
PM Girard, C D'Ham, J Cadet and S Boiteux
The yOgg1 protein of Saccharomyces cerevisiae is a DNA glycosylase/AP lyase
that excises guanine lesions such as 7,8-dihydro-8-oxoguanine (8- OxoG) and
2,6-diamino-4-hydroxy-5-N-methylformamidopyrimidine (me-Fapy- G) and
incises apurinic/apyrimidinic sites (AP sites) in damaged DNA. The yOgg1
protein displays a marked preference for DNA duplexes containing 8-OxoG or
AP sites placed opposite cytosine. In this paper, we show that yOgg1 can
also excise an adenine lesion, 7,8-dihydro-8- oxoadenine (8-OxoA), when
paired with cytosine or 5-methylcytosine. In contrast, yOgg1 does not
release 8-OxoA when placed opposite thymine, adenine, guanine or uracil.
The specificity constants (Kcat/Km) for repair of 8-OxoG/C and 8-OxoA/C
duplexes are (50 +/- 18) x 10(-3) and (13 +/- 3) x 10(-3)/min/nM,
respectively. The catalytic mechanism for strand cleavage at 8-OxoA/C
involves excision of 8-OxoA by the DNA glycosylase activity of yOgg1,
followed by incision at the newly formed AP site via a beta-elimination
reaction. Furthermore, cleavage of 8- OxoA/C involves formation of a
reaction intermediate that is converted into a stable covalent adduct in
the presence of sodium borohydride (NaBH4). The yOgg1 protein binds
strongly to the 8-OxoA/C duplex, as demonstrated by an apparent
dissociation constant (Kdapp) value of 45 nM, as determined by gel mobility
shift assay. In contrast, the yOgg1 protein has a very low binding affinity
for the 8-OxoA/T duplex, a Kdapp value of 680 nM, which in turn can explain
the lack of repair of 8-OxoA in this duplex. The capacity of other DNA
glycosylases/AP lyases to repair 8-OxoA has also been investigated. The
results show that human hOgg1 protein efficiently repairs 8-OxoA placed
opposite cytosine or 5-methylcytosine. On the other hand, the Fpg protein
of Escherichia coli cleaves 8-OxoA/C at a very slow rate as compared with
yOgg1.
ARTICLES
Opposite base-dependent excision of 7,8-dihydro-8-oxoadenine by the Ogg1 protein of Saccharomyces cerevisiae
Departement de Radiobiologie et Radiopathologie, UMR217 CNRS-CEA, Radiobiologie Moleculaire et Cellulaire, Fontenay aux Roses, France.
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