Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: The role of apurinic sites

Dhrubajyoti Chakravarti, Jill C. Felling, Ercole Cavalieri, Eleanor G Rogan

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

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 sties generated by loss of hydrocarbon- DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.

Original languageEnglish (US)
Pages (from-to)10422-10426
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume92
Issue number22
DOIs
StatePublished - Oct 24 1995

Fingerprint

Aromatic Hydrocarbons
DNA Adducts
Papilloma
Codon
ras Genes
Skin
Mutation
9,10-Dimethyl-1,2-benzanthracene
Hydrocarbons
Hordeolum
Exons
Benzo(a)pyrene
Epoxy Compounds
Point Mutation
Mutagenesis
Neoplasms
DNA

ASJC Scopus subject areas

  • General

Cite this

@article{da5b79eb96174930920120b8f4b81131,
title = "Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: The role of apurinic sites",
abstract = "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 sties generated by loss of hydrocarbon- DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.",
author = "Dhrubajyoti Chakravarti and Felling, {Jill C.} and Ercole Cavalieri and Rogan, {Eleanor G}",
year = "1995",
month = "10",
day = "24",
doi = "10.1073/pnas.92.22.10422",
language = "English (US)",
volume = "92",
pages = "10422--10426",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "22",

}

TY - JOUR

T1 - Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas

T2 - The role of apurinic sites

AU - Chakravarti, Dhrubajyoti

AU - Felling, Jill C.

AU - Cavalieri, Ercole

AU - Rogan, Eleanor G

PY - 1995/10/24

Y1 - 1995/10/24

N2 - 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 sties generated by loss of hydrocarbon- DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.

AB - 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 sties generated by loss of hydrocarbon- DNA adducts is responsible for transforming mutations leading to papillomas in mouse skin.

UR - http://www.scopus.com/inward/record.url?scp=0028785807&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028785807&partnerID=8YFLogxK

U2 - 10.1073/pnas.92.22.10422

DO - 10.1073/pnas.92.22.10422

M3 - Article

C2 - 7479797

AN - SCOPUS:0028785807

VL - 92

SP - 10422

EP - 10426

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 22

ER -