Impact of folate deficiency on DNA stability

Susan Joyce Duthie, S Narayanan, G M Brand, Lynn Peters Pirie, George Grant

Research output: Contribution to journalArticle

169 Citations (Scopus)

Abstract

Convincing evidence links folate deficiency with colorectal cancer incidence. Currently, it is believed that folate deficiency affects DNA stability principally through two potential pathways. 5,10-Methylenetetrahydrofolate donates a methyl group to uracil, converting it to thymine, which is used for DNA synthesis and repair. If folate is limited, imbalances in the DNA precursor pool occur, and uracil may be misincorporated into DNA. Subsequent misincorporation and repair may lead to double strand breaks, chromosomal damage and cancer. Moreover, folate affects gene expression by regulating cellular S-adenosylmethionine (SAM) levels. 5-Methyltetrahydrofolate serves as methyl donor in the remethylation of homocysteine to methionine, which in turn is converted to SAM. SAM methylates specific cytosines in DNA, and this regulates gene transcription. As a consequence of folate deficiency, cellular SAM is depleted, which in turn induces DNA hypomethylation and potentially induces proto-oncogene expression leading to cancer. Data from several model systems supporting these mechanisms are reviewed here. There is convincing evidence that folate modulates both DNA synthesis and repair and DNA hypomethylation with altered gene expression in vitro. The data from in vivo experiments in rodents is more difficult to interpret because of variations in the animal and experimental systems used and the influence of tissue specificity and folate metabolism. Most importantly, the confounding effects of nutrient-gene interactions, together with the identification of polymorphisms in key enzyme systems and the influence that these have on folate metabolism and DNA stability, must be considered when interpreting evidence from human studies.

Original languageEnglish
Pages (from-to)2444S-2449S
Number of pages6
JournalThe Journal of Nutrition
Volume132
Issue number8
Publication statusPublished - Aug 2002

Keywords

  • folate
  • DNA stability
  • methylation
  • nutrition
  • HAMSTER OVARY CELLS
  • DEOXYNUCLEOTIDE POOL IMBALANCE
  • FOLIC-ACID DEFICIENCY
  • URACIL MISINCORPORATION
  • COLON-CANCER
  • IN-VITRO
  • C677T POLYMORPHISM
  • COLORECTAL-CANCER
  • EXCISION-REPAIR
  • GENOMIC DNA
  • folate
  • DNA stability
  • methylation

Cite this

Duthie, S. J., Narayanan, S., Brand, G. M., Pirie, L. P., & Grant, G. (2002). Impact of folate deficiency on DNA stability. The Journal of Nutrition, 132(8), 2444S-2449S.

Impact of folate deficiency on DNA stability. / Duthie, Susan Joyce; Narayanan, S ; Brand, G M ; Pirie, Lynn Peters; Grant, George.

In: The Journal of Nutrition, Vol. 132, No. 8, 08.2002, p. 2444S-2449S.

Research output: Contribution to journalArticle

Duthie, SJ, Narayanan, S, Brand, GM, Pirie, LP & Grant, G 2002, 'Impact of folate deficiency on DNA stability' The Journal of Nutrition, vol. 132, no. 8, pp. 2444S-2449S.
Duthie SJ, Narayanan S, Brand GM, Pirie LP, Grant G. Impact of folate deficiency on DNA stability. The Journal of Nutrition. 2002 Aug;132(8):2444S-2449S.
Duthie, Susan Joyce ; Narayanan, S ; Brand, G M ; Pirie, Lynn Peters ; Grant, George. / Impact of folate deficiency on DNA stability. In: The Journal of Nutrition. 2002 ; Vol. 132, No. 8. pp. 2444S-2449S.
@article{75d2976fd7324df6874d2b20e5c8cfd2,
title = "Impact of folate deficiency on DNA stability",
abstract = "Convincing evidence links folate deficiency with colorectal cancer incidence. Currently, it is believed that folate deficiency affects DNA stability principally through two potential pathways. 5,10-Methylenetetrahydrofolate donates a methyl group to uracil, converting it to thymine, which is used for DNA synthesis and repair. If folate is limited, imbalances in the DNA precursor pool occur, and uracil may be misincorporated into DNA. Subsequent misincorporation and repair may lead to double strand breaks, chromosomal damage and cancer. Moreover, folate affects gene expression by regulating cellular S-adenosylmethionine (SAM) levels. 5-Methyltetrahydrofolate serves as methyl donor in the remethylation of homocysteine to methionine, which in turn is converted to SAM. SAM methylates specific cytosines in DNA, and this regulates gene transcription. As a consequence of folate deficiency, cellular SAM is depleted, which in turn induces DNA hypomethylation and potentially induces proto-oncogene expression leading to cancer. Data from several model systems supporting these mechanisms are reviewed here. There is convincing evidence that folate modulates both DNA synthesis and repair and DNA hypomethylation with altered gene expression in vitro. The data from in vivo experiments in rodents is more difficult to interpret because of variations in the animal and experimental systems used and the influence of tissue specificity and folate metabolism. Most importantly, the confounding effects of nutrient-gene interactions, together with the identification of polymorphisms in key enzyme systems and the influence that these have on folate metabolism and DNA stability, must be considered when interpreting evidence from human studies.",
keywords = "folate, DNA stability, methylation, nutrition, HAMSTER OVARY CELLS, DEOXYNUCLEOTIDE POOL IMBALANCE, FOLIC-ACID DEFICIENCY, URACIL MISINCORPORATION, COLON-CANCER, IN-VITRO, C677T POLYMORPHISM, COLORECTAL-CANCER, EXCISION-REPAIR, GENOMIC DNA, folate , DNA stability , methylation",
author = "Duthie, {Susan Joyce} and S Narayanan and Brand, {G M} and Pirie, {Lynn Peters} and George Grant",
year = "2002",
month = "8",
language = "English",
volume = "132",
pages = "2444S--2449S",
journal = "The Journal of Nutrition",
issn = "0022-3166",
publisher = "American Society for Nutrition",
number = "8",

}

TY - JOUR

T1 - Impact of folate deficiency on DNA stability

AU - Duthie, Susan Joyce

AU - Narayanan, S

AU - Brand, G M

AU - Pirie, Lynn Peters

AU - Grant, George

PY - 2002/8

Y1 - 2002/8

N2 - Convincing evidence links folate deficiency with colorectal cancer incidence. Currently, it is believed that folate deficiency affects DNA stability principally through two potential pathways. 5,10-Methylenetetrahydrofolate donates a methyl group to uracil, converting it to thymine, which is used for DNA synthesis and repair. If folate is limited, imbalances in the DNA precursor pool occur, and uracil may be misincorporated into DNA. Subsequent misincorporation and repair may lead to double strand breaks, chromosomal damage and cancer. Moreover, folate affects gene expression by regulating cellular S-adenosylmethionine (SAM) levels. 5-Methyltetrahydrofolate serves as methyl donor in the remethylation of homocysteine to methionine, which in turn is converted to SAM. SAM methylates specific cytosines in DNA, and this regulates gene transcription. As a consequence of folate deficiency, cellular SAM is depleted, which in turn induces DNA hypomethylation and potentially induces proto-oncogene expression leading to cancer. Data from several model systems supporting these mechanisms are reviewed here. There is convincing evidence that folate modulates both DNA synthesis and repair and DNA hypomethylation with altered gene expression in vitro. The data from in vivo experiments in rodents is more difficult to interpret because of variations in the animal and experimental systems used and the influence of tissue specificity and folate metabolism. Most importantly, the confounding effects of nutrient-gene interactions, together with the identification of polymorphisms in key enzyme systems and the influence that these have on folate metabolism and DNA stability, must be considered when interpreting evidence from human studies.

AB - Convincing evidence links folate deficiency with colorectal cancer incidence. Currently, it is believed that folate deficiency affects DNA stability principally through two potential pathways. 5,10-Methylenetetrahydrofolate donates a methyl group to uracil, converting it to thymine, which is used for DNA synthesis and repair. If folate is limited, imbalances in the DNA precursor pool occur, and uracil may be misincorporated into DNA. Subsequent misincorporation and repair may lead to double strand breaks, chromosomal damage and cancer. Moreover, folate affects gene expression by regulating cellular S-adenosylmethionine (SAM) levels. 5-Methyltetrahydrofolate serves as methyl donor in the remethylation of homocysteine to methionine, which in turn is converted to SAM. SAM methylates specific cytosines in DNA, and this regulates gene transcription. As a consequence of folate deficiency, cellular SAM is depleted, which in turn induces DNA hypomethylation and potentially induces proto-oncogene expression leading to cancer. Data from several model systems supporting these mechanisms are reviewed here. There is convincing evidence that folate modulates both DNA synthesis and repair and DNA hypomethylation with altered gene expression in vitro. The data from in vivo experiments in rodents is more difficult to interpret because of variations in the animal and experimental systems used and the influence of tissue specificity and folate metabolism. Most importantly, the confounding effects of nutrient-gene interactions, together with the identification of polymorphisms in key enzyme systems and the influence that these have on folate metabolism and DNA stability, must be considered when interpreting evidence from human studies.

KW - folate

KW - DNA stability

KW - methylation

KW - nutrition

KW - HAMSTER OVARY CELLS

KW - DEOXYNUCLEOTIDE POOL IMBALANCE

KW - FOLIC-ACID DEFICIENCY

KW - URACIL MISINCORPORATION

KW - COLON-CANCER

KW - IN-VITRO

KW - C677T POLYMORPHISM

KW - COLORECTAL-CANCER

KW - EXCISION-REPAIR

KW - GENOMIC DNA

KW - folate

KW - DNA stability

KW - methylation

M3 - Article

VL - 132

SP - 2444S-2449S

JO - The Journal of Nutrition

JF - The Journal of Nutrition

SN - 0022-3166

IS - 8

ER -