Folate deficiency provides protection against colon carcinogenesis in DNA polymerase beta haploinsufficient mice.

Abstract

Aging and DNA polymerase beta deficiency (beta-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 beta-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 beta-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 beta-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 beta-pol haploinsufficient mice.

• Authors: Lisa F Ventrella-Lucente, Archana Unnikrishnan, Amanda B Pilling, Hiral V Patel, Deepa Kushwaha, Alan A Dombkowski, Eva M Schmelz, Diane C Cabelof, Ahmad R Heydari
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 285 Issue 25 Pg. 19246-58 (Jun 18 2010) ISSN: 1083-351X [Electronic] United States
• PMID: 20404327 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Vitamins
• DNA Polymerase beta
• 1,2-Dimethylhydrazine

Topics

• 1,2-Dimethylhydrazine (pharmacology)
• Animal Feed
• Animals
• Apoptosis
• Colonic Neoplasms (drug therapy, prevention & control)
• DNA Damage
• DNA Polymerase beta (genetics)
• DNA Repair
• Folic Acid Deficiency (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Oligonucleotide Array Sequence Analysis
• Vitamins (metabolism)