DNA polymerases II and V mediate respectively mutagenic (-2 frameshift) and error-free bypass of a single N-2-acetylaminofluorene adduct.
The NarI sequence represents a strong mutation hot spot for -2 frameshift mutations induced by N-2-acetylaminofluorene (AAF), a strong chemical carcinogen. Only when bound to the third (underlined) guanine (5'-GGCGCC-->GGCC) can AAF trigger frameshift mutations, suggesting the involvement of a slipped replication intermediate with a two-nucleotide bulge. While base substitutions induced by UV light or abasic sites require DNA polymerase V (Pol V; umuDC), the AAF-induced -2 frameshift pathway requires DNA polymerase II, the polB gene product. Interestingly, error-free bypass of the G-AAF adduct requires Pol V. The genes encoding both Pol II and Pol V are induced by the SOS regulon, a co-ordinated cellular response to environmental stress. A given lesion, G-AAF, can thus be bypassed by two SOS-controlled DNA polymerases (II and V), generating mutagenic (-2 frameshifts) and error-free replication products respectively. Therefore both Pol II and Pol V can compete for the blocked replication intermediate in the vicinity of the lesion and engage in replication by transiently replacing the replicative DNA Pol III. Our data suggest that, in order to cope with the large diversity of existing DNA lesions, cells use a single or a combination of translesional DNA polymerases to achieve translesion synthesis.
Fuchs
R P
RP
UPR 9003, CNRS Cancerogenese et Mutagenese Moleculaire et Structurale, ESBS and IRCAD, Strasbourg 67400, France. fuchs@esbs.u-strasb.fr
Koffel-Schwartz
N
N
Pelet
S
S
Janel-Bintz
R
R
Napolitano
R
R
Becherel
O J
OJ
Broschard
T H
TH
Burnouf
D Y
DY
Wagner
J
J
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D001483:Base Sequence; D002273:Carcinogens / Q000378:metabolism; D018736:DNA Adducts / Q000235:genetics / Q000378:metabolism* / Q000528:radiation effects; D004257:DNA Polymerase II / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication / Q000528:radiation effects; D004269:DNA, Bacterial / Q000096:biosynthesis / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics / Q000528:radiation effects; D029968:Escherichia coli Proteins; D016368:Frameshift Mutation / Q000235:genetics* / Q000528:radiation effects; D005798:Genes, Bacterial / Q000235:genetics; D016296:Mutagenesis / Q000235:genetics* / Q000528:radiation effects; D014466:Ultraviolet Rays
D002273:Carcinogens; D018736:DNA Adducts; D004269:DNA, Bacterial; D029968:Escherichia coli Proteins; D015073:2-Acetylaminofluorene; D004257:DNA Polymerase II; C120926:DNA polymerase V, E coli; D004259:DNA-Directed DNA Polymerase