Imbalanced Base Excision Repair in Response to Folate Deficiency Is Accelerated by Polymerase β Haploinsufficiency

Cabelof, Diane C.; Raffoul, Julian J.; Nakamura, Jun; Kapoor, Diksha; Abdalla, Hala; Heydari, Ahmad R.

doi:10.1074/jbc.m405185200

Cited by 38 publications

(54 citation statements)

References 42 publications

(60 reference statements)

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“…We also show an increased incidence of microscopic adenoma and liver tumor formation in wild type mice upon DMH treatment when folate is deficient. These data indicate, in conjunction with our previous studies (17), that the pathway responsible for repairing these damages may be ineffective when folate is limiting. Based on the above findings, it is inviting to suggest that folate deficiency mimics BER deficiency perhaps by over-whelming the capacity of BER through inhibition of its ratedetermining enzyme, DNA polymerase ␤.…”

Section: Discussionsupporting

confidence: 87%

“…Although the mechanism by which folate deficiency increases cancer risk is not clear, folate deficiency has been shown to induce damage repaired via the BER pathway (17). Branda et al (10) have demonstrated that folate-deficient animals are less able to repair DNA damage induced by alkylating agents.…”

Section: Discussionmentioning

confidence: 99%

“…Diets and Carcinogenic Treatment-After acclimation for 7 days, wild type (WT) and ␤-pol ϩ/Ϫ mice were randomly assigned to two dietary groups: a folate-adequate (FA) or folatedeficient (FD) AIN93G-purified isoenergetic diet (Dyets, Inc., Lehigh Valley, PA) as described previously (17). The FA group received a folate-adequate diet containing 2 mg/kg of folic acid.…”

Section: Methodsmentioning

confidence: 99%

“…The animals' food intake and body weight were monitored weekly. Folate deficiency for 8 weeks did not affect body weight, whereas it reduced the plasma folate level by 90% as determined by a SimulTRAC-SNB radioassay kit for vitamin B 12 ( 57 Co) and folate ( 125 I) per the manufacturer's protocol (ICN Diagnostics, Orangeburg, NY) as described previously (17). In addition, under these conditions we observed an approximate 40% decrease in colon folate concentration when folate was deficient, a finding similar to those of others (29).…”

Section: Induction Of Acf Formation In Dna Polymerase ␤ Haploinsufficmentioning

confidence: 99%

“…We have reported previously that folate deficiency overwhelms the capacity of BER through the inhibition of upregulation of ␤-pol (17). It is feasible that the inability to induce ␤-pol when folate is deficient results in a functional BER deficiency, providing a logical explanation for the phenotype induced by folate deficiency.…”

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confidence: 97%

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Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Ventrella-Lucente¹,

Unnikrishnan²,

Pilling³

et al. 2010

Journal of Biological Chemistry

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Aging and DNA polymerase ␤ deficiency (␤-pol ؉/؊ ) interact to accelerate the development of malignant lymphomas and adenocarcinoma and increase tumor bearing load in mice. Folate deficiency (FD) has been shown to induce DNA damage repaired via the base excision repair (BER) pathway. We anticipated that FD and BER deficiency would interact to accelerate aberrant crypt foci (ACF) formation and tumor development in ␤-pol haploinsufficient animals. FD resulted in a significant increase in ACF formation in wild type (WT) animals exposed to 1,2-dimethylhydrazine, a known colon and liver carcinogen; however, FD reduced development of ACF in ␤-pol haploinsufficient mice. Prolonged feeding of the FD diet resulted in advanced ACF formation and liver tumors in wild type mice. However, FD attenuated onset and progression of ACF and prevented liver tumorigenesis in ␤-pol haploinsufficient mice, i.e. FD provided protection against tumorigenesis in a BER-deficient environment in all tissues where 1,2-dimethylhydrazine exerts its damage. Here we show a distinct down-regulation in DNA repair pathways, e.g. BER, nucleotide excision repair, and mismatch repair, and decline in cell proliferation, as well as an up-regulation in poly(ADP-ribose) polymerase, proapoptotic genes, and apoptosis in colons of FD ␤-pol haploinsufficient mice.Folate deficiency is an important public health concern because of the role folate plays in the development of many different health problems, including neural tube defects, cardiovascular disease, Alzheimer disease, and cancer, specifically colon cancer. It has been proposed that the carcinogenic properties of folate deficiency may be related to a decrease in DNA methylation, perhaps as a function of reduced S-adenosylmethionine levels, an increase in the uracil content of DNA, or an increase in oxidative stress by alterations in thiol switches. Folate deficiency has also been shown to increase (in cells, animal models, and humans) levels of single strand breaks (1-5), micronucleus formation (6, 7), chromosomal aberration (8, 9), and mutation frequency (10, 11), all potentially downstream effects of high levels of uracil in DNA and oxidative damage to DNA.The DNA repair pathway for removal of uracil and oxidized bases is the base excision repair (BER) 2 pathway. The BER pathway is believed to repair small, non-helix-distorting lesions in the DNA. It has been estimated to be responsible for the repair of as many as one million nucleotides per cell per day (12), stressing its importance in the maintenance of genomic stability. It has been suggested that BER has evolved in response to in vivo exposure of DNA to reactive oxygen species and endogenous alkylation, and that this pathway suppresses spontaneous mutagenesis (13). In the initial elucidation of the BER pathway the following steps were involved: (i) removal of the damaged base by a DNA glycosylase; (ii) incision of the phosphate backbone by an endonuclease; (iii) synthesis of new DNA by a polymerase; (iv) excision of the deoxyribose phosphate moie...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Induction Of Acf Formation In Dna Polymerase ␤ Haploinsufficmentioning

confidence: 99%

mentioning

confidence: 97%

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Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Ventrella-Lucente¹,

Unnikrishnan²,

Pilling³

et al. 2010

Journal of Biological Chemistry

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A sensitive biochemical assay for the detection of uracil

Cabelof

Nakamura

Heydari

2005

Environ and Mol Mutagen

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We have developed a sensitive new assay for the detection of uracil in DNA. The assay described here is an adaptation to the highly sensitive aldehydic slot blot (ASB) assay developed by Nakamura et al. (Nakamura et al. 1998: Cancer Res 58:222-225) in which aldehydic DNA lesions (ADLs) are detected through binding of a biotinylated aldehydic reactive probe to DNA. The uracil DNA glycosylase (UDG)-coupled ASB assay uses uracil-DNA glycosylase to generate an abasic site, which is subsequently detected by the ASB methodology. The ability to modify this technique for the detection of uracil has these advantages: small quantities of DNA are required (4 microg of DNA); the assay is adaptable to DNA from both cells and tissues; sensitivity is as good as that achieved by less accessible methodologies, like gas chromatography-mass spectroscopy (GC-MS); DNA strand breaks are not a confounding variable; preexisting aldehydic lesions are blocked through the use of methoxyamine; variation is very low (<3%); radioactive isotopes are not required; and the assay is easy to establish and involves only equipment and reagents that are inexpensive and readily available. This assay is conceivably adaptable to the detection of other DNA base lesions through the use of a variety of DNA glycosylases.

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AOP report: Development of an adverse outcome pathway for oxidative DNA damage leading to mutations and chromosomal aberrations

Cho

Allemang

Audebert

et al. 2022

Environ and Mol Mutagen

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The Genetic Toxicology Technical Committee (GTTC) of the Health and Environmental Sciences Institute (HESI) is developing adverse outcome pathways (AOPs) that describe modes of action leading to potentially heritable genomic damage. The goal was to enhance the use of mechanistic information in genotoxicity assessment by building empirical support for the relationships between relevant molecular initiating events (MIEs) and regulatory endpoints in genetic toxicology.Herein, we present an AOP network that links oxidative DNA damage to two adverse outcomes (AOs): mutations and chromosomal aberrations. We collected empirical evidence from the literature to evaluate the key event relationships between the MIE and the AOs, and assessed the weight of evidence using the modified Bradford-Hill criteria for causality. Oxidative DNA damage is constantly induced and repaired in

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Imbalanced Base Excision Repair in Response to Folate Deficiency Is Accelerated by Polymerase β Haploinsufficiency

Cited by 38 publications

References 42 publications

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

Folate Deficiency Provides Protection against Colon Carcinogenesis in DNA Polymerase β Haploinsufficient Mice

A sensitive biochemical assay for the detection of uracil

AOP report: Development of an adverse outcome pathway for oxidative DNA damage leading to mutations and chromosomal aberrations

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