Genotoxicity of aflatoxin B1: Evidence for a recombination-mediated mechanism in

Sengstag, Christian; Weibel, Béatrice; Fasullo, Michael

doi:10.1016/s0928-4346(97)89843-x

Cited by 21 publications

(56 citation statements)

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“…7 that summarizes our current understanding of the roles of DNA repair and checkpoint pathways in the elimination and/or tolerance of the DNA adducts produced by AFB 1 in S. cerevisiae. Early studies indicated that AFB 1 is strongly recombinogenic but only weakly mutagenic in yeast (87). Our work offers an explanation of these observations, in that wild-type cells readily and faithfully repair AFB 1 -induced damage using homologous recombination and nucleotide excision repair, consistent with the role of recombinational repair in the repair of AFB 1 -induced DNA damage in another study (48).…”

Section: Discussionsupporting

confidence: 83%

Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage

Guo

Breeden

Zarbl

et al. 2005

Molecular and Cellular Biology

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Aflatoxin B 1 (AFB 1 ) is a human hepatotoxin and hepatocarcinogen produced by the mold Aspergillus flavus. In humans, AFB 1 is primarily bioactivated by cytochrome P450 1A2 (CYP1A2) and 3A4 to a genotoxic epoxide that forms N 7 -guanine DNA adducts. A series of yeast haploid mutants defective in DNA repair and cell cycle checkpoints were transformed with human CYP1A2 to investigate how these DNA adducts are repaired. Cell survival and mutagenesis following aflatoxin B 1 treatment was assayed in strains defective in nucleotide excision repair (NER) (rad14), postreplication repair (PRR) (rad6, rad18, mms2, and rad5), homologous recombinational repair (HRR) (rad51 and rad54), base excision repair (BER) (apn1 apn2), nonhomologous end-joining (NHEJ) (yku70), mismatch repair (MMR) (pms1), translesion synthesis (TLS) (rev3), and checkpoints (mec1-1, mec1-1 rad53, rad9, and rad17). Together our data suggest the involvement of homologous recombination and nucleotide excision repair, postreplication repair, and checkpoints in the repair and/or tolerance of AFB 1 -induced DNA damage in the yeast model. Rev3 appears to mediate AFB 1 -induced mutagenesis when error-free pathways are compromised. The results further suggest unique roles for Rad5 and abasic endonuclease-dependent DNA intermediates in regulating AFB 1 -induced mutagenicity.Mutagenic substances, including many environmental contaminants, are structurally diverse and range from simple compounds such as methylating agents to bulky DNA damaging agents (57). Differences in DNA repair capacity may play an important role in determination of individual susceptibility to endogenous and exogenous mutagens (88). DNA repair and mutagenesis have been less well studied for bulky mutagens, partly because the majority of them require efficient bioactivation by biotransformation enzymes that are absent in many in vitro study models (35).A yeast model has been established in this study to delineate the mechanisms involved in the elimination and/or tolerance of DNA damage produced by a bulky mutagen, aflatoxin B 1 (AFB 1 ). A natural toxin produced by the common fungal mold Aspergillus flavus (21), AFB 1 is one of the most potent mutagens ever characterized in eukaryotes (12,31,62). It requires biotransformation by cytochrome P450 (CYP450)-dependent monooxygenases to the reactive, yet highly unstable AFB 1 -8,9-exo-epoxide (AFBO) to become toxic and carcinogenic (21). AFBO can react with the N 7 guanine residue of DNA to form an unstable trans-8,9-dihydro-(N 7 -guanyl)-9-hydroxy-aflatoxin B 1 adduct (AFB 1 -N 7 -Gua) that is thought to either be removed hydrolytically to form an abasic (AP) site or to undergo a hydrolytic reaction that opens the guanine imidazole ring, forming a stable and persistent formamidopyrimidine (AFB 1 -FAPY) derivative (61,93). Studies have shown that human CYP1A2 (hCYP1A2) is the high-affinity CYP450 enzyme active at the low AFB 1 concentrations typically encountered in dietary exposures (26). Consequences of AFB 1 -induced DNA lesions include chromoso...

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Section: Discussionsupporting

confidence: 83%

Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage

Guo

Breeden

Zarbl

et al. 2005

Molecular and Cellular Biology

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“…In yeast, AFB 1 can induce mitotic, homologous recombination resulting in heteroallelic gene conversion and translocations (Sengstag et al, 1996). After yeast cells are exposed to low doses of AFB 1 in the expected range of human exposure, there is a strong stimulation of recombination but not mutation (unpublished data).…”

Section: Introductionmentioning

confidence: 94%

“…The 2 URA3 plasmids pMK637 (this work) or pSB229 (Eugster et al, 1992), containing hCYP1A2ϩhOR and hCYP1A1ϩhOR cDNAs, respectively, or the LEU2 plasmid pCS512 (Sengstag et al, 1996), containing hCYP1A1ϩhOR cDNAs, were first introduced into yeast strains by DNA transformation to metabolically activate the AFB 1 and benzo-(a)-pyrene-7,8-dihydrodiol (BaP-DHD; Klebe et al, 1983). The 2 URA3 plasmid pCS316, containing the hCYP1A1ϩhOR cDNA in the opposite orientation as in pSB229 (Eugster et al, 1992), was introduced into YB110, YB324, and YB335 to measure AFB 1 -associated translocations in mec1 checkpoint mutants.…”

Section: Media and Strainsmentioning

confidence: 99%

“…We measured the frequency AFB 1 , EMS, and BaP-DHD-associated translocations and drug toxicity in the rad mutants, YB195pSB229 (rad51) and YB150pCS512 (rad1); checkpoint mutants, YB324pCS316 (sml1, mec1) and YB325pCS316 (mec1); and the Rad ϩ proficient strain YB110pCS316, as previously described (Sengstag et al, 1996). YB195, YB150, YB324, and YB325 transformants were grown in YM His-Ade-Trp-Lys and YB110 transformants in YM His-Ade-Trp.…”

Section: Measurements Of Dna Damage-associated Recombination Frequencmentioning

confidence: 99%

“…AFB 1 is a mutagen in Saccharomyces cerevisiae (Sengstag et al, 1996), Escherichia coli, rainbow trout, mice, rat and human cells (reviewed in Smela et al, 2001), and a recombinagen in yeast and in human cells (Stettler and Sengstag, 2001). In yeast, AFB 1 can induce mitotic, homologous recombination resulting in heteroallelic gene conversion and translocations (Sengstag et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional Response of Yeast to Aflatoxin B₁: Recombinational Repair InvolvingRAD51andRAD1

Keller-Seitz

Certa

Sengstag

et al. 2004

MBoC

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The potent carcinogen aflatoxin B 1 is a weak mutagen but a strong recombinagen in Saccharomyces cerevisiae. Aflatoxin B 1 exposure greatly increases frequencies of both heteroallelic recombination and chromosomal translocations. We analyzed the gene expression pattern of diploid cells exposed to aflatoxin B 1 using high-density oligonucleotide arrays comprising specific probes for all 6218 open reading frames. Among 183 responsive genes, 46 are involved in either DNA repair or in control of cell growth and division. Inducible growth control genes include those in the TOR signaling pathway and SPO12, whereas PKC1 is downregulated. Eleven of the 15 inducible DNA repair genes, including RAD51, participate in recombination. Survival and translocation frequencies are reduced in the rad51 diploid after aflatoxin B 1 exposure. In mec1 checkpoint mutants, aflatoxin B 1 exposure does not induce RAD51 expression or increase translocation frequencies; however, when RAD51 is constitutively overexpressed in the mec1 mutant, aflatoxin B 1 exposure increased translocation frequencies. Thus the transcriptional profile after aflatoxin B 1 exposure may elucidate the genotoxic properties of aflatoxin B 1 .

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The molecular mechanism of aflatoxin B1–induced liver cancer: Is mitotic recombination involved?

Sengstag

1997

Mol. Carcinog.

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Genotoxicity of aflatoxin B1: Evidence for a recombination-mediated mechanism in

Cited by 21 publications

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Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage

Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage

Transcriptional Response of Yeast to Aflatoxin B₁: Recombinational Repair InvolvingRAD51andRAD1

The molecular mechanism of aflatoxin B1–induced liver cancer: Is mitotic recombination involved?

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Genotoxicity of aflatoxin B1: Evidence for a recombination-mediated mechanism in

Cited by 21 publications

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Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage

Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage

Transcriptional Response of Yeast to Aflatoxin B1: Recombinational Repair InvolvingRAD51andRAD1

The molecular mechanism of aflatoxin B1–induced liver cancer: Is mitotic recombination involved?

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Transcriptional Response of Yeast to Aflatoxin B₁: Recombinational Repair InvolvingRAD51andRAD1