Translesion Synthesis Past Estrogen-Derived DNA Adducts by Human DNA Polymerases and 
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- 作者：Naomi Suzuki ; Shinji Itoh ; Kinning Poon ; Chikahide Masutani ; Fumio Hanaoka ; Haruo Ohmori ; Itsuo Yoshizawa ; and Shinya Shibutani
- 刊名：Biochemistry
- 出版年：2004
- 出版时间：May 25, 2004
- 年：2004
- 卷：43
- 期：20
- 页码：6304 - 6311
- 全文大小：170K
- 年卷期：v.43,no.20(May 25, 2004)
- ISSN：1520-4995
文摘
Newly discovered human DNA polymerase (pol) 
and 
are highly expressed in thereproductive organs, such as testis, ovary, and uterus, where steroid hormones are produced. Becausetreatment with estrogen increases the risk of developing breast, ovary, and endometrial cancers, miscodingevents occurring at model estrogen-derived DNA adducts were explored using pol and a truncated formof human pol (pol 
C). These enzymes bypassed N2-[3-methoxyestra-1,3,5(10)-trien-6-yl]-2'-deoxyguanosine (dG-N2-3MeE) and N6-[3-methoxyestra-1,3,5(10)-trien-6-yl]-2'-deoxyadenosine (dA-N6-3MeE), which were embedded in site-specifically modified oligodeoxynucleotide templates. Quantitativeanalysis of base substitutions and deletions occurring at the lesion site showed that pol C was moreefficient at incorporating dCMP opposite the dG-N2-3MeE lesion than pol . Surprisingly, the frequencyof translesion synthesis beyond the dC
dG-N2-3MeE pair was 13% of the normal dCdG pair and was 4and 6 orders of magnitude higher than that of dC(+)-trans-dG-N2-benzo[a]pyrene and dCdG-C8-acetylaminofluorene pairs, respectively, suggesting that dG-N2-3MeE is a natural substrate for pol . Incontrast, the bypass frequency beyond the dTdA-N6-3MeE pair was 7 orders of magnitude less than thatfor the normal dTdA pair. dA-N6-3MeE is a more miscoding lesion than dG-N2-3MeE. Pol promotedincorporation of dAMP and dCMP at the dA-N6-3MeE lesion, while with pol C, deletions were morefrequently observed, along with incorporation of dAMP and dCMP opposite the lesion. These observationswere also supported by steady-state kinetic studies. When taken together, the properties of pol and are consistent with the mutagenic events attributed to estrogen-derived DNA adducts.
and are highly expressed in thereproductive organs, such as testis, ovary, and uterus, where steroid hormones are produced. Becausetreatment with estrogen increases the risk of developing breast, ovary, and endometrial cancers, miscodingevents occurring at model estrogen-derived DNA adducts were explored using pol and a truncated formof human pol (pol C). These enzymes bypassed N2-[3-methoxyestra-1,3,5(10)-trien-6-yl]-2'-deoxyguanosine (dG-N2-3MeE) and N6-[3-methoxyestra-1,3,5(10)-trien-6-yl]-2'-deoxyadenosine (dA-N6-3MeE), which were embedded in site-specifically modified oligodeoxynucleotide templates. Quantitativeanalysis of base substitutions and deletions occurring at the lesion site showed that pol C was moreefficient at incorporating dCMP opposite the dG-N2-3MeE lesion than pol . Surprisingly, the frequencyof translesion synthesis beyond the dCdG-N2-3MeE pair was 13% of the normal dCdG pair and was 4and 6 orders of magnitude higher than that of dC(+)-trans-dG-N2-benzo[a]pyrene and dCdG-C8-acetylaminofluorene pairs, respectively, suggesting that dG-N2-3MeE is a natural substrate for pol . Incontrast, the bypass frequency beyond the dTdA-N6-3MeE pair was 7 orders of magnitude less than thatfor the normal dTdA pair. dA-N6-3MeE is a more miscoding lesion than dG-N2-3MeE. Pol promotedincorporation of dAMP and dCMP at the dA-N6-3MeE lesion, while with pol C, deletions were morefrequently observed, along with incorporation of dAMP and dCMP opposite the lesion. These observationswere also supported by steady-state kinetic studies. When taken together, the properties of pol and are consistent with the mutagenic events attributed to estrogen-derived DNA adducts.