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

Susan J. Duthie, George Grant, Lynn P. Pirie, Amanda J. Watson, Geoffrey P. Margison

Research output: Contribution to journalArticle

26 Citations (Scopus)

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 (similar to 80%; P < 0.0001), whole blood (similar to 40%; P < 0.0001), and tissue folate (between 25% and 60% depending on the tissue sampled; P < 0.05); increased plasma total homocysteine (similar to 35%; P < 0.05); and decreased S-adenosylmethionine to S-adenosylhomocysteine concentrations (similar to 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 (similar to 27%; P < 0.03) and MGMT (similar to 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. Cancer Prev Res; 3(1); 92-100. (c) 2010 AACR.

Original languageEnglish
Pages (from-to)92-100
Number of pages9
JournalCancer Prevention Research
Volume3
Issue number1
DOIs
Publication statusPublished - Jan 2010

Keywords

  • randomized clinical-trial
  • colorectal-cancer
  • dietary-folate
  • folic-acid
  • excision-repair
  • uracil misincorporation
  • damage
  • risk
  • supplementation
  • association
  • folic acid deficiency in rat
  • DNA repair
  • MGMT
  • 8-oxoguanine-DNA glycosylase
  • DNA methylation

Cite this

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. / Duthie, Susan J.; Grant, George; Pirie, Lynn P.; Watson, Amanda J.; Margison, Geoffrey P.

In: Cancer Prevention Research, Vol. 3, No. 1, 01.2010, p. 92-100.

Research output: Contribution to journalArticle

Duthie, Susan J. ; Grant, George ; Pirie, Lynn P. ; Watson, Amanda J. ; Margison, Geoffrey P. / 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. In: Cancer Prevention Research. 2010 ; Vol. 3, No. 1. pp. 92-100.
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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 (similar to 80{\%}; P < 0.0001), whole blood (similar to 40{\%}; P < 0.0001), and tissue folate (between 25{\%} and 60{\%} depending on the tissue sampled; P < 0.05); increased plasma total homocysteine (similar to 35{\%}; P < 0.05); and decreased S-adenosylmethionine to S-adenosylhomocysteine concentrations (similar to 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 (similar to 27{\%}; P < 0.03) and MGMT (similar to 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. Cancer Prev Res; 3(1); 92-100. (c) 2010 AACR.",
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AU - Margison, Geoffrey P.

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N2 - 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 (similar to 80%; P < 0.0001), whole blood (similar to 40%; P < 0.0001), and tissue folate (between 25% and 60% depending on the tissue sampled; P < 0.05); increased plasma total homocysteine (similar to 35%; P < 0.05); and decreased S-adenosylmethionine to S-adenosylhomocysteine concentrations (similar to 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 (similar to 27%; P < 0.03) and MGMT (similar to 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. Cancer Prev Res; 3(1); 92-100. (c) 2010 AACR.

AB - 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 (similar to 80%; P < 0.0001), whole blood (similar to 40%; P < 0.0001), and tissue folate (between 25% and 60% depending on the tissue sampled; P < 0.05); increased plasma total homocysteine (similar to 35%; P < 0.05); and decreased S-adenosylmethionine to S-adenosylhomocysteine concentrations (similar to 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 (similar to 27%; P < 0.03) and MGMT (similar to 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. Cancer Prev Res; 3(1); 92-100. (c) 2010 AACR.

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KW - risk

KW - supplementation

KW - association

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KW - DNA repair

KW - MGMT

KW - 8-oxoguanine-DNA glycosylase

KW - DNA methylation

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