2010
DOI: 10.1074/jbc.m109.069807
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Abstract: 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 ty… Show more

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Cited by 16 publications
(17 citation statements)
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References 41 publications
(23 reference statements)
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“…Data from our laboratory and others suggest that apoptotic and DNA repair pathways might be potential targets of folate deficiency [8, 10]. In other words, increased accumulation of DNA damages such as DNA strand breaks, increased somatic mutations and chromosomal aberrations observed during folate deficiency can be attributed to defective DNA repair.…”
Section: Introductionmentioning
confidence: 99%
“…Data from our laboratory and others suggest that apoptotic and DNA repair pathways might be potential targets of folate deficiency [8, 10]. In other words, increased accumulation of DNA damages such as DNA strand breaks, increased somatic mutations and chromosomal aberrations observed during folate deficiency can be attributed to defective DNA repair.…”
Section: Introductionmentioning
confidence: 99%
“…Under normal dietary conditions, b-pol heterozygosity increases the number of DMH-induced ACF, but when the B-vitamin folate is limiting in the diet, b-pol heterozygosity protects from these tumors. This appears to be due to a robust apoptotic response when folate is depleted in the heterozygous model, suggesting requirement of intact DNA damage responses [14]. This report is not unlike the protective effect of homozygous Ku80 deletion on APC min tumorigenesis [16], which is a p53-dependent effect.…”
Section: Base Excision Repairmentioning
confidence: 43%
“…Other tissues show no increase in mutagenicity in the absence of a chemical challenge. However, in response to chemical exposure or aging, heterozygous loss of b-pol acts as a significant modifier of penetrance: increased mutagenesis in response to DMS [10]; accelerated strand break accumulation in response to oxidative stress [10] and folate depletion [13]; increased aberrant crypt formation (ACF) in response to DMH [14]; increased liver tumors in response to DMH [14]; accelerated spontaneous tumorigenesis (lymphoma and adenocarcinoma) [15]; and an accelerated rate of aging [15]. This model presents an interesting dichotomy with respect to risk (not unlike several of the Polb Yes [27] Single strand break accumulation in response to acute oxidative stress; increased LacI mutation frequency in response to DMS; increased spontaneous chromosomal aberrations, specifically centromere separation [10] Heterozygosity intensifies the single strand break phenotype induced by folate depletion [13] Accelerated rate of aging; age-dependent lymphoma incidence increased sevenfold; twofold increase in hypoploidy in lymphcytes.…”
Section: Base Excision Repairmentioning
confidence: 99%
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“…Moreover, the authors found that the combination of folate deficiency and Polb haploinsufficiency activated apoptotic signaling pathways, which indicated that the cells preferred to undergo cell death rather than attempt repair. This consequently reduced the onset and progression of preneoplastic lesions in colon tissue [Ventrella-Lucente et al, 2010]. The Polb haploinsufficient mouse is also reported to be a model for Down's syndrome and premature aging [Patterson and Cabelof, 2011].…”
Section: The X Family Of Dna Polymerasesmentioning
confidence: 99%