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The effect of the human O(6)-alkylgu...

Minnick, Dana Thorne.

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The effect of the human O(6)-alkylguanine-DNA alkyltransferase on the mutational specificity of bis -chloroethylnitrosourea in the Chinese hamster ovary cell line, D422.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The effect of the human O(6)-alkylguanine-DNA alkyltransferase on the mutational specificity of bis -chloroethylnitrosourea in the Chinese hamster ovary cell line, D422./
作者:	Minnick, Dana Thorne.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 1992,
面頁冊數:	201 p.
附註:	Source: Dissertation Abstracts International, Volume: 53-11, Section: B, page: 5624.
Contained By:	Dissertation Abstracts International53-11B.
標題:	Environmental science. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=9307233

The effect of the human O(6)-alkylguanine-DNA alkyltransferase on the mutational specificity of bis -chloroethylnitrosourea in the Chinese hamster ovary cell line, D422.
Minnick, Dana Thorne.

The effect of the human O(6)-alkylguanine-DNA alkyltransferase on the mutational specificity of bis -chloroethylnitrosourea in the Chinese hamster ovary cell line, D422. - Ann Arbor : ProQuest Dissertations & Theses, 1992 - 201 p.

Source: Dissertation Abstracts International, Volume: 53-11, Section: B, page: 5624.

Thesis (Ph.D.)--Case Western Reserve University (Health Sciences), 1992.

The mutational specificity of the alkylating agent bis-chloroethylnitrosourea (BCNU) was analyzed at the endogenous hemizygous adenine phosphoribosyl transferase (aprt) gene of the O$\sp6$-alkyguanine-DNA alkyltransferase-deficient Chinese hamster ovary cell line, D422. A one hour treatment of the CHO cells with 50 uM BCNU resulted in a toxicity level of 62% and induced mutation at this target with a frequency of 32.1 mutants/10$\sp6$ survivors (six-fold above background). Analysis of 49 BCNU-induced mutants at the DNA sequence level revealed that BCNU induced primarily base substitutions. The predominant BCNU-induced mutations were G:C $\to$ T:A transversions, which comprised 51% (25/49) of the mutations; while, G:C $\to$ A:T transitions, expected from miscoding of O$\sp6$-alkylguanine for thymine, were the second most frequent mutation recovered representing 16.3% (8/49) of the mutations. Furthermore, two "hotspots" for BCNU-induced G:C $\to$ T:A transversions were observed, which involved different surrounding DNA sequences but identical helix parameters when analyzed by an application of Calladine's Rules.Subjects--Topical Terms:

677245
Environmental science.

The effect of the human O(6)-alkylguanine-DNA alkyltransferase on the mutational specificity of bis -chloroethylnitrosourea in the Chinese hamster ovary cell line, D422.
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100 1 $a Minnick, Dana Thorne. $3 3285186
245 1 4 $a The effect of the human O(6)-alkylguanine-DNA alkyltransferase on the mutational specificity of bis -chloroethylnitrosourea in the Chinese hamster ovary cell line, D422.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 1992
300 $a 201 p.
500 $a Source: Dissertation Abstracts International, Volume: 53-11, Section: B, page: 5624.
500 $a Adviser: W. David Sedwick.
502 $a Thesis (Ph.D.)--Case Western Reserve University (Health Sciences), 1992.
520 $a The mutational specificity of the alkylating agent bis-chloroethylnitrosourea (BCNU) was analyzed at the endogenous hemizygous adenine phosphoribosyl transferase (aprt) gene of the O$\sp6$-alkyguanine-DNA alkyltransferase-deficient Chinese hamster ovary cell line, D422. A one hour treatment of the CHO cells with 50 uM BCNU resulted in a toxicity level of 62% and induced mutation at this target with a frequency of 32.1 mutants/10$\sp6$ survivors (six-fold above background). Analysis of 49 BCNU-induced mutants at the DNA sequence level revealed that BCNU induced primarily base substitutions. The predominant BCNU-induced mutations were G:C $\to$ T:A transversions, which comprised 51% (25/49) of the mutations; while, G:C $\to$ A:T transitions, expected from miscoding of O$\sp6$-alkylguanine for thymine, were the second most frequent mutation recovered representing 16.3% (8/49) of the mutations. Furthermore, two "hotspots" for BCNU-induced G:C $\to$ T:A transversions were observed, which involved different surrounding DNA sequences but identical helix parameters when analyzed by an application of Calladine's Rules.
520 $a In an effort to address the importance of the O$\sp6$-alkylguanine mediated lesions in BCNU-induced mutation in CHO D422, and to determine the probable role of these adducts as promutational lesions in the generation of the G:C $\to$ T:A and G:C $\to$ A:T base substitutions, the human $O\sp6$-alkylguanine-DNA alkyltransferase cDNA (MGMT) was transfected into CHO D422. The alkyltransferase-transformed cell line exhibited 100-fold protection against BCNU-induced toxicity and a maximal four-fold reduction in the overall mutation frequency at the aprt gene target in comparison to the parental cell line. When the mutational specificity of BCNU in the alkyltransferase-transformed cell line was compared to that of the parental cell line, the frequence of G:C $\to$ T:A transversions was reduced 25-fold in the alkyltransferase-transformed cell line. Furthermore, G:C $\to$ A:T transitions were reduced 6-fold. These findings suggest that both the G:C $\to$ T:A transversions and G:C$\to$A:T transitions were O$\sp6$-alkylguanine mediated mutations. In the presence of proficient repair of the BCNU-induced O$\sp6$-alkylguanine lesions, T:A $\to$ G:C transversions emerged as the predominant BCNU-induced mutation, comprising 45% (23/51) of the recovered mutations. In addition, these mutations occurred as multiple isolates at several sites suggesting that the focus of BCNU induced mutations at T:A base pairs was DNA sequence dependent.
590 $a School code: 0499.
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792 $a 1992
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