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Nucleotide excision repair and trans...

Chen, Dandan.

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Nucleotide excision repair and translesion synthesis of DNA adducts derived from the equine estrogen metabolite 4-hydroxyequilenin.

紀錄類型:	書目-語言資料,印刷品 : Monograph/item
正題名/作者:	Nucleotide excision repair and translesion synthesis of DNA adducts derived from the equine estrogen metabolite 4-hydroxyequilenin./
作者:	Chen, Dandan.
面頁冊數:	341 p.
附註:	Adviser: Nicholas E. Geacintov.
Contained By:	Dissertation Abstracts International68-01B.
標題:	Chemistry, Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3247354

Nucleotide excision repair and translesion synthesis of DNA adducts derived from the equine estrogen metabolite 4-hydroxyequilenin.
Chen, Dandan.

Nucleotide excision repair and translesion synthesis of DNA adducts derived from the equine estrogen metabolite 4-hydroxyequilenin. - 341 p.

Adviser: Nicholas E. Geacintov.

Thesis (Ph.D.)--New York University, 2007.

Hormone replacement therapy (HRT) is widely used among postmenopausal women to alleviate undesired symptoms. The equine estrogens, equilin and equilenin, comprise 25--50% of the estrogens in a widely prescribed HRT formulation. A recent large-scale clinical trial has shown that women undergoing HRT are at a greater risk of developing breast cancer and tumors in reproductive organs than untreated women. A genotoxic pathway leading to tumor development has been postulated that involves damage to cellular DNA by estrogen catechol metabolites. The equine estrogens are metabolized by mammalian cytochrome P450 in vivo to the chemically reactive catechol 4-hydroequilenin (4-OHEN) that is rapidly autooxidized to o-quinones that, in turn, readily react with the nucleobases of DNA to form unusual cyclic base adducts. The objectives of this work were to develop methods for synthesizing and characterizing site-specifically modified oligonucleotides containing single, stereochemically defined lesions derived from reactions of 4-OHEN with DNA. The yield of 4-OHEN-cytosine adducts is predominant, while only a minor proportion of adenine adducts are formed, with practically no guanine adducts except in special sequence contexts. Two pairs of stereoisomeric nucleobase adducts are formed in each case that are distinguishable by their circular dichroism characteristics. The 4-OHEN-dC adducts destabilize double-stranded DNA more severely than the 4-OHEN-dA adducts, and are more susceptible to excision by human nucleotide excision repair (NER) enzymes in cell-free-extracts in a stereochemistry-dependent manner. In contrast, NER catalyzed by prokaryotic UvrABC nuclease is independent of stereochemistry, but the 4-OHEN-dC adducts are excised more efficiently than 4-OHEN-dA adducts. The 4-OHEN-dC adducts are bypasses in an error-prone manner by replicative and several different Y-family polymerases.Subjects--Topical Terms:

1017722
Chemistry, Biochemistry.

Nucleotide excision repair and translesion synthesis of DNA adducts derived from the equine estrogen metabolite 4-hydroxyequilenin.
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520 $a Hormone replacement therapy (HRT) is widely used among postmenopausal women to alleviate undesired symptoms. The equine estrogens, equilin and equilenin, comprise 25--50% of the estrogens in a widely prescribed HRT formulation. A recent large-scale clinical trial has shown that women undergoing HRT are at a greater risk of developing breast cancer and tumors in reproductive organs than untreated women. A genotoxic pathway leading to tumor development has been postulated that involves damage to cellular DNA by estrogen catechol metabolites. The equine estrogens are metabolized by mammalian cytochrome P450 in vivo to the chemically reactive catechol 4-hydroequilenin (4-OHEN) that is rapidly autooxidized to o-quinones that, in turn, readily react with the nucleobases of DNA to form unusual cyclic base adducts. The objectives of this work were to develop methods for synthesizing and characterizing site-specifically modified oligonucleotides containing single, stereochemically defined lesions derived from reactions of 4-OHEN with DNA. The yield of 4-OHEN-cytosine adducts is predominant, while only a minor proportion of adenine adducts are formed, with practically no guanine adducts except in special sequence contexts. Two pairs of stereoisomeric nucleobase adducts are formed in each case that are distinguishable by their circular dichroism characteristics. The 4-OHEN-dC adducts destabilize double-stranded DNA more severely than the 4-OHEN-dA adducts, and are more susceptible to excision by human nucleotide excision repair (NER) enzymes in cell-free-extracts in a stereochemistry-dependent manner. In contrast, NER catalyzed by prokaryotic UvrABC nuclease is independent of stereochemistry, but the 4-OHEN-dC adducts are excised more efficiently than 4-OHEN-dA adducts. The 4-OHEN-dC adducts are bypasses in an error-prone manner by replicative and several different Y-family polymerases.
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