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Characterization of an apurinic/apyr...

Raffoul, Julian John.

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Characterization of an apurinic/apyrimidinic endonuclease heterozygous knockout mouse: Identifying nutrient-gene and gene-environment interactions on DNA repair.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Characterization of an apurinic/apyrimidinic endonuclease heterozygous knockout mouse: Identifying nutrient-gene and gene-environment interactions on DNA repair./
Author:	Raffoul, Julian John.
Description:	290 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1788.
Contained By:	Dissertation Abstracts International65-04B.
Subject:	Health Sciences, Nutrition. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3130361
ISBN:	049677610X

Characterization of an apurinic/apyrimidinic endonuclease heterozygous knockout mouse: Identifying nutrient-gene and gene-environment interactions on DNA repair.
Raffoul, Julian John.

Characterization of an apurinic/apyrimidinic endonuclease heterozygous knockout mouse: Identifying nutrient-gene and gene-environment interactions on DNA repair. - 290 p.

Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1788.

Thesis (Ph.D.)--Wayne State University, 2004.

In this dissertation, transgenic mice containing a heterozygous gene-targeted deletion of the apurinic/apyrimidinic (AP) endonuclease (APE) gene (Apex +/-) were utilized to determine the phenotype observed in response to loss of APE at baseline levels and in response to nutrient and environmental interventions. APE is a multifunctional protein involved in the maintenance of genomic integrity and in the regulation of gene expression. APE is the major 5'-endonuclease in base excision repair (BER) and is known as ref-1, for redox factor-1, a redox activator of cellular transcription factors. Apex +/- mice display a 40--50% reduction in APE mRNA, protein, and 5'-endonuclease activity in all tissues studied, while BER was tissue-specific. BER correlated with AP site DNA binding, DNA polymerase beta (beta-pol) protein, and p53 activation levels. A mechanism of redox-regulated BER is proposed.

ISBN: 049677610XSubjects--Topical Terms:

1017801
Health Sciences, Nutrition.

Characterization of an apurinic/apyrimidinic endonuclease heterozygous knockout mouse: Identifying nutrient-gene and gene-environment interactions on DNA repair.
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100 1 $a Raffoul, Julian John. $3 1905989
245 1 0 $a Characterization of an apurinic/apyrimidinic endonuclease heterozygous knockout mouse: Identifying nutrient-gene and gene-environment interactions on DNA repair.
300 $a 290 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-04, Section: B, page: 1788.
500 $a Adviser: Ahmad R. Heydari.
502 $a Thesis (Ph.D.)--Wayne State University, 2004.
520 $a In this dissertation, transgenic mice containing a heterozygous gene-targeted deletion of the apurinic/apyrimidinic (AP) endonuclease (APE) gene (Apex +/-) were utilized to determine the phenotype observed in response to loss of APE at baseline levels and in response to nutrient and environmental interventions. APE is a multifunctional protein involved in the maintenance of genomic integrity and in the regulation of gene expression. APE is the major 5'-endonuclease in base excision repair (BER) and is known as ref-1, for redox factor-1, a redox activator of cellular transcription factors. Apex +/- mice display a 40--50% reduction in APE mRNA, protein, and 5'-endonuclease activity in all tissues studied, while BER was tissue-specific. BER correlated with AP site DNA binding, DNA polymerase beta (beta-pol) protein, and p53 activation levels. A mechanism of redox-regulated BER is proposed.
520 $a In response to folate deficiency, BER/beta-pol and APE protein and activity levels did not change; yet, BER initiation was increased. Apex+/- mice fed a folate-deficient diet displayed a significant increase in the level of AP sites, with a concomitant decrease in single strand breaks. Folate deficiency is believed to cause a dysregulation of the BER pathway and may provide an important mechanistic explanation for the increased cancer risk associated with inadequate dietary folate. In response to 2-nitropropane (2-NP, 100 mg/kg), an oxidizing agent and hepatocarcinogen, a significant increase in DNA damage was observed in wild-type (Apex +/-) mice. A corresponding upregulation in the levels of APE, beta-pol and BER were also observed, indicating that BER is damage-inducible in vivo. Aging resulted in a progressive decrease in BER/beta-pol, while the level and activity of APE increased. Aged mice exposed to 2-NP were unable to induce BER, and this inability to respond to damage correlated with decreases in both APE and beta-pol. A similar phenotype was observed in Apex+/- mice. These results strongly support the notion that beta-pol is the rate-determining enzyme in BER, while APE functions as a damage-response facilitator. A reduction/dysregulation in the damage-induced BER response may render an organism susceptible to genomic instability. Future research may identify BER deficiency or dysregulation as a risk factor for disease such as cancer.
590 $a School code: 0254.
650 4 $a Health Sciences, Nutrition. $3 1017801
650 4 $a Biology, Molecular. $3 1017719
690 $a 0570
690 $a 0307
710 2 0 $a Wayne State University. $3 975058
773 0 $t Dissertation Abstracts International $g 65-04B.
790 1 0 $a Heydari, Ahmad R., $e advisor
790 $a 0254
791 $a Ph.D.
792 $a 2004
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3130361