Folate deficiency alters hepatic and colon MGMT and OGG-1 DNA repair protein expression in rats but has no effect on genome-wide DNA methylation.

2.50
Hdl Handle:
http://hdl.handle.net/10541/109312
Title:
Folate deficiency alters hepatic and colon MGMT and OGG-1 DNA repair protein expression in rats but has no effect on genome-wide DNA methylation.
Authors:
Duthie, Susan J; Grant, George; Pirie, Lynn P; Watson, Amanda J; Margison, Geoffrey P
Abstract:
Folate deficiency is implicated in human colon cancer. The effects of feeding rats a folate-deficient diet for 24 weeks on DNA damage (8-oxo-7,8-dihydroguanine), DNA repair [O(6)-methylguanine-DNA methyltransferase (MGMT) and 8-oxoguanine-DNA glycosylase (OGG-1) activity], and epigenetic parameters (genome-wide cytosine methylation and indices of cellular methylation status) were investigated. Relative to control diet, the folate-deficient diet resulted in significantly reduced levels of serum ( approximately 80%; P < 0.0001), whole blood ( approximately 40%; P < 0.0001), and tissue folate (between 25% and 60% depending on the tissue sampled; P < 0.05); increased plasma total homocysteine ( approximately 35%; P < 0.05); and decreased S-adenosylmethionine to S-adenosylhomocysteine concentrations ( approximately 11%; P < 0.05). There was no significant change in the levels of 5-methyldeoxycytidine in liver or colon DNA, nor in the activity of liver DNA cytosine methyltransferase. However, there were significant increases in 8-oxo-7,8-dihydroguanine (P < 0.001) in lymphocyte DNA and in levels of the DNA repair proteins OGG-1 ( approximately 27%; P < 0.03) and MGMT ( approximately 25%; P < 0.003) in the liver, but not in the colon. This may reflect the ability of the liver, but not the colon, to upregulate DNA repair enzymes in response to either elevated DNA damage or an imbalance in the nucleotide precursor pool. These results show that folate deficiency can significantly modulate DNA damage and DNA repair, providing mechanisms by which it plays a role in the etiology of human cancer. We speculate that the inability of colon tissue to respond to folate deficiency occurs in humans and may increase the potential for malignant transformation.
Affiliation:
Rowett Institute of Nutrition and Health, University of Aberdeen, United Kingdom. s.duthie@abdn.ac.uk
Citation:
Folate deficiency alters hepatic and colon MGMT and OGG-1 DNA repair protein expression in rats but has no effect on genome-wide DNA methylation. 2010, 3 (1):92-100 Cancer Prev Res
Journal:
Cancer Prevention Research
Issue Date:
Jan-2010
URI:
http://hdl.handle.net/10541/109312
DOI:
10.1158/1940-6207.CAPR-09-0231
PubMed ID:
20051376
Type:
Article
Language:
en
ISSN:
1940-6215
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorDuthie, Susan Jen
dc.contributor.authorGrant, Georgeen
dc.contributor.authorPirie, Lynn Pen
dc.contributor.authorWatson, Amanda Jen
dc.contributor.authorMargison, Geoffrey Pen
dc.date.accessioned2010-08-09T16:24:15Z-
dc.date.available2010-08-09T16:24:15Z-
dc.date.issued2010-01-
dc.identifier.citationFolate deficiency alters hepatic and colon MGMT and OGG-1 DNA repair protein expression in rats but has no effect on genome-wide DNA methylation. 2010, 3 (1):92-100 Cancer Prev Resen
dc.identifier.issn1940-6215-
dc.identifier.pmid20051376-
dc.identifier.doi10.1158/1940-6207.CAPR-09-0231-
dc.identifier.urihttp://hdl.handle.net/10541/109312-
dc.description.abstractFolate deficiency is implicated in human colon cancer. The effects of feeding rats a folate-deficient diet for 24 weeks on DNA damage (8-oxo-7,8-dihydroguanine), DNA repair [O(6)-methylguanine-DNA methyltransferase (MGMT) and 8-oxoguanine-DNA glycosylase (OGG-1) activity], and epigenetic parameters (genome-wide cytosine methylation and indices of cellular methylation status) were investigated. Relative to control diet, the folate-deficient diet resulted in significantly reduced levels of serum ( approximately 80%; P < 0.0001), whole blood ( approximately 40%; P < 0.0001), and tissue folate (between 25% and 60% depending on the tissue sampled; P < 0.05); increased plasma total homocysteine ( approximately 35%; P < 0.05); and decreased S-adenosylmethionine to S-adenosylhomocysteine concentrations ( approximately 11%; P < 0.05). There was no significant change in the levels of 5-methyldeoxycytidine in liver or colon DNA, nor in the activity of liver DNA cytosine methyltransferase. However, there were significant increases in 8-oxo-7,8-dihydroguanine (P < 0.001) in lymphocyte DNA and in levels of the DNA repair proteins OGG-1 ( approximately 27%; P < 0.03) and MGMT ( approximately 25%; P < 0.003) in the liver, but not in the colon. This may reflect the ability of the liver, but not the colon, to upregulate DNA repair enzymes in response to either elevated DNA damage or an imbalance in the nucleotide precursor pool. These results show that folate deficiency can significantly modulate DNA damage and DNA repair, providing mechanisms by which it plays a role in the etiology of human cancer. We speculate that the inability of colon tissue to respond to folate deficiency occurs in humans and may increase the potential for malignant transformation.en
dc.language.isoenen
dc.subject.meshAnimals-
dc.subject.meshColon-
dc.subject.meshDNA Damage-
dc.subject.meshDNA Glycosylases-
dc.subject.meshDNA Methylation-
dc.subject.meshDNA Repair-
dc.subject.meshFolic Acid Deficiency-
dc.subject.meshLiver-
dc.subject.meshMale-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.subject.meshRats-
dc.titleFolate deficiency alters hepatic and colon MGMT and OGG-1 DNA repair protein expression in rats but has no effect on genome-wide DNA methylation.en
dc.typeArticleen
dc.contributor.departmentRowett Institute of Nutrition and Health, University of Aberdeen, United Kingdom. s.duthie@abdn.ac.uken
dc.identifier.journalCancer Prevention Researchen
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