RELATING AROMATIC HYDROCARBON-INDUCED DNA-ADDUCTS AND C-H-RAS MUTATIONS IN MOUSE SKIN PAPILLOMAS - THE ROLE OF APURINIC SITES
RELATING AROMATIC HYDROCARBON-INDUCED DNA-ADDUCTS AND C-H-RAS MUTATIONS IN MOUSE SKIN PAPILLOMAS - THE ROLE OF APURINIC SITES
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DOI：
10.1073/pnas.92.22.10422
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发表时间：
1995-10-24
影响因子：
11.1
通讯作者：
ROGAN, EG
中科院分区：
文献类型：
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作者：
CHAKRAVARTI, D;PELLING, JC;ROGAN, EG
小鼠皮肤肿瘤含有活化的c-H-ras癌基因，通常由外显子1的12和13密码子以及外显子2的59和61密码子的点突变引起。非编码无嘌呤位点的诱变可以通过DNA错误复制产生G -> T和A -> T转运，脱氧腺苷在无嘌呤位点对面更频繁地插入。几种芳香烃在小鼠皮肤中诱导乳头状瘤，并测定了c-H-ras基因的突变，以阐明DNA加合物、无嘌呤位点和ras癌基因突变之间的关系。二苯并-[a， 1]芘（DB[a, 1]P）、DB[a, 1]P-11,12-二氢二醇、抗DB[a， 1]P-11,12-二醇-13,14-环氧化合物、DB[a， 1]P-8,9-二氢二醇、7,12-二甲基苯[a]蒽（DMBA）和1,2,3,4-四氢-DMBA均可诱导c-H-ras癌基因密码子61中的CAA -> CTA突变。苯并[a]芘诱导54%的肿瘤发生密码子13的GGC -> GTC突变，15%的肿瘤发生密码子61的CAA -> CTA突变。每种碳氢化合物引起的突变模式与其DNA加合物的谱相关联。例如，DB[a，l]P和DMBA主要在脱氧腺苷的N-3和/或N-7上形成DNA加合物，脱氧腺苷通过去嘌呤作用从DNA中丢失，产生无嘌呤位点。因此，这些结果支持了一种假设，即由碳氢- dna加合物的缺失引起的未修复的无尿嘧啶位点的错误复制是导致小鼠皮肤乳头状瘤的转化突变的原因。
Mouse skin tumors contain activated c-H-ras oncogenes, often caused by point mutations at codons 12 and 13 in exon 1 and codons 59 and 61 in exon 2. Mutagenesis by the noncoding apurinic sites can produce G --> T and A --> T transversions by DNA misreplication with more frequent insertion of deoxyadenosine opposite the apurinic site. Papillomas were induced in mouse skin by several aromatic hydrocarbons, and mutations in the c-H-ras gene were determined to elucidate the relationship among DNA adducts, apurinic sites, and ras oncogene mutations. Dibenzo-[a,l]pyrene (DB[a,l]P), DB [a,l]P-11,12-dihydrodiol, anti-DB [a,l]P-11,12-diol-13,14-epoxide, DB [a,l]P-8,9-dihydrodiol, 7,12-dimethylbenz[a]anthracene (DMBA), and 1,2,3,4-tetrahydro-DMBA consistently induced a CAA --> CTA mutation in codon 61 of the c-H-ras oncogene. Benzo[a]pyrene induced a GGC --> GTC mutation in codon 13 in 54% of tumors and a CAA --> CTA mutation in codon 61 in 15%. The pattern of mutations induced by each hydrocarbon correlated with its profile of DNA adducts. For example, both DB[a,l]P and DMBA primarily form DNA adducts at the N-3 and/or N-7 of deoxyadenosine that are lost from the DNA by depurination, generating apurinic sites. Thus, these results support the hypothesis that misreplication of unrepaired apurinic sites generated by loss of hydrocarbon-DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.