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首页> 外文期刊>Molecular and Cellular Biology >Expression of a Human Cytochrome P450 in Yeast Permits Analysis of Pathways for Response to and Repair of Aflatoxin-Induced DNA Damage
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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

机译：人细胞色素P450在酵母中的表达允许对黄曲霉毒素诱导的DNA损伤进行应答和修复的途径分析

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Aflatoxin B1 (AFB1) is a human hepatotoxin and hepatocarcinogen produced by the mold Aspergillus flavus. In humans, AFB1 is primarily bioactivated by cytochrome P450 1A2 (CYP1A2) and 3A4 to a genotoxic epoxide that forms N7-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 B1 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 AFB1-induced DNA damage in the yeast model. Rev3 appears to mediate AFB1-induced mutagenesis when error-free pathways are compromised. The results further suggest unique roles for Rad5 and abasic endonuclease-dependent DNA intermediates in regulating AFB1-induced mutagenicity.
机译：黄曲霉毒素B 1 （AFB 1 ）是由黄曲霉（Aspergillus flavus）霉菌产生的人肝毒素和肝致癌物。在人类中，AFB 1 主要被细胞色素P450 1A2（CYP1A2）和3A4生物激活为遗传毒性的环氧化物，形成N 7 -鸟嘌呤DNA加合物。用人类CYP1A2转化了一系列DNA修复和细胞周期检查点有缺陷的酵母单倍体突变体，以研究如何修复这些DNA加合物。黄曲霉毒素B 1 处理后的细胞存活和诱变在核苷酸切除修复（NER）（ rad14 ），复制后修复（PRR）（ rad6 < / em>， rad18 ， mms2 和 rad5 ），同源重组修复（HRR）（ rad51 和< em> rad54 ），碱基切除修复（BER）（ apn1 apn2 ），非同源末端连接（NHEJ）（ yku70 ），错配修复（MMR） （ pms1 ），跨病变合成（TLS）（ rev3 ）和检查点（ mec1 - 1 ， mec1-1 rad53 ， rad9 和 rad17 ）。我们的数据一起表明酵母模型中AFB 1 诱导的DNA损伤的修复和/或耐受性涉及同源重组和核苷酸切除修复，复制后修复以及检查点。当无错途径受损时，Rev3似乎可以介导AFB 1 诱导的诱变。结果进一步表明，Rad5和无碱基内切酶依赖性DNA中间体在调节AFB 1 致突变性中具有独特作用。

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