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A role for DNA polymerase V in G->T mutations from the major benzo[a]pyrene N^2-dG adduct when studied in a 5'-TG@?T sequence in E. coli [An article from: DNA Repair]
Book Details
Author(s)J. Yin, K.Y. Seo, E.L. Loechler
PublisherElsevier
ISBN / ASINB000RQZMC8
ISBN-13978B000RQZMC2
AvailabilityAvailable for download now
MarketplaceUnited States 🇺🇸
Description
This digital document is a journal article from DNA Repair, published by Elsevier in 2004. The article is delivered in HTML format and is available in your Amazon.com Media Library immediately after purchase. You can view it with any web browser.
Description:
Benzo[a]pyrene (B[a]P), a potent mutagen/carcinogen, is metabolically activated to (+)-anti-B[a]PDE, which induces a full spectrum of mutations (e.g. GC->TA, GC->AT, etc.) principally via its major adduct [+ta]-B[a]P-N^2-dG. Recent findings suggest that different lesion bypass DNA polymerases may be involved in different mutagenic pathways, which is the subject of this report. [+ta]-B[a]P-N^2-dG built into a plasmid in a 5'-TG@?T sequence gives approximately equal numbers of G->T and G->A mutations when host E. coli are UV irradiated prior to transformation, so this sequence context was chosen to investigate what DNA polymerases are involved in G->T versus G->A mutations. G->T mutations decline (>10-fold) if E. coli either are not UV-irradiated or are deficient in DNA polymerase V (@DumuD/C), demonstrating a role for damage-inducible DNA Pol V in a G->T pathway. G->T mutations are not affected by transformation into E. coli deficient in either DNA polymerases II or IV. While the work herein was in progress, Lenne-Samuel et al. [Mol. Microbiol. 38 (2000) 299] built the same adduct into a plasmid in a 5'-GG@?A sequence, and showed that the frequency of G->T mutations was similar in UV-irradiated and unirradiated host E. coli cells, suggesting no involvement by damage-inducible, lesion bypass DNA polymerases (i.e., not II, IV or V); furthermore, a role for DNA Pol V was explicitly ruled out. The easiest way to reconcile the findings of Lenne-Samuel et al. with the findings herein is if two G->T mutagenic pathways exist for [+ta]-B[a]P-N^2-dG, where sequence context dictates which pathway is followed. In contrast to the G->T mutations, herein G->A mutations from [+ta]-B[a]P-N^2-dG in the 5'-TG@?T sequence context are shown not to be affected by UV-irradiation of host E. coli, and are not dependent on DNA Pol V, or Pol II, Pol IV, or the damage-inducible, but SOS-independent UVM system. Published studies, however, have shown that G->A mutations are usually enhanced by UV-irradiation of host E. coli prior to the introduction of plasmids either site-specifically modified with [+ta]-B[a]P-N^2-dG or randomly adducted with (+)-anti-B[a]PDE; both findings imply the involvement of a lesion-bypass DNA polymerase. These disparate results suggest the existence of two G->A mutagenic pathways for [+ta]-B[a]P-N^2-dG as well, although confirmation of this awaits further study. In conclusion, a comparison between the evidence presented herein and published findings suggests the existence of two distinct mutagenic pathways for both G->T and G->A mutations from [+ta]-B[a]P-N^2-dG, where in each case one pathway is not damage-inducible and not dependent on a lesion-bypass DNA polymerase, while the second pathway is damage-inducible and dependent on a lesion-bypass DNA polymerase. Furthermore, DNA sequence context appears to dictate which pathway (as defined by the involvement of different DNA polymerases) is followed in each case.
Description:
Benzo[a]pyrene (B[a]P), a potent mutagen/carcinogen, is metabolically activated to (+)-anti-B[a]PDE, which induces a full spectrum of mutations (e.g. GC->TA, GC->AT, etc.) principally via its major adduct [+ta]-B[a]P-N^2-dG. Recent findings suggest that different lesion bypass DNA polymerases may be involved in different mutagenic pathways, which is the subject of this report. [+ta]-B[a]P-N^2-dG built into a plasmid in a 5'-TG@?T sequence gives approximately equal numbers of G->T and G->A mutations when host E. coli are UV irradiated prior to transformation, so this sequence context was chosen to investigate what DNA polymerases are involved in G->T versus G->A mutations. G->T mutations decline (>10-fold) if E. coli either are not UV-irradiated or are deficient in DNA polymerase V (@DumuD/C), demonstrating a role for damage-inducible DNA Pol V in a G->T pathway. G->T mutations are not affected by transformation into E. coli deficient in either DNA polymerases II or IV. While the work herein was in progress, Lenne-Samuel et al. [Mol. Microbiol. 38 (2000) 299] built the same adduct into a plasmid in a 5'-GG@?A sequence, and showed that the frequency of G->T mutations was similar in UV-irradiated and unirradiated host E. coli cells, suggesting no involvement by damage-inducible, lesion bypass DNA polymerases (i.e., not II, IV or V); furthermore, a role for DNA Pol V was explicitly ruled out. The easiest way to reconcile the findings of Lenne-Samuel et al. with the findings herein is if two G->T mutagenic pathways exist for [+ta]-B[a]P-N^2-dG, where sequence context dictates which pathway is followed. In contrast to the G->T mutations, herein G->A mutations from [+ta]-B[a]P-N^2-dG in the 5'-TG@?T sequence context are shown not to be affected by UV-irradiation of host E. coli, and are not dependent on DNA Pol V, or Pol II, Pol IV, or the damage-inducible, but SOS-independent UVM system. Published studies, however, have shown that G->A mutations are usually enhanced by UV-irradiation of host E. coli prior to the introduction of plasmids either site-specifically modified with [+ta]-B[a]P-N^2-dG or randomly adducted with (+)-anti-B[a]PDE; both findings imply the involvement of a lesion-bypass DNA polymerase. These disparate results suggest the existence of two G->A mutagenic pathways for [+ta]-B[a]P-N^2-dG as well, although confirmation of this awaits further study. In conclusion, a comparison between the evidence presented herein and published findings suggests the existence of two distinct mutagenic pathways for both G->T and G->A mutations from [+ta]-B[a]P-N^2-dG, where in each case one pathway is not damage-inducible and not dependent on a lesion-bypass DNA polymerase, while the second pathway is damage-inducible and dependent on a lesion-bypass DNA polymerase. Furthermore, DNA sequence context appears to dictate which pathway (as defined by the involvement of different DNA polymerases) is followed in each case.
