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

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

doi:10.1074/jbc.m109.069807

Lisa F Ventrella-Lucente, Archana Unnikrishnan + Show 7 more

Open Access

https://doi.org/10.1074/jbc.m109.069807

Copy DOI

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.

Highlights

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, colon cancer
Based on the striking similarities between DNA damage induced by folate deficiency and that induced by a reduction in base excision repair (BER) capacity, we suggest a strong association between BER and folate
Induction of ACF Formation in DNA Polymerase ␤ Haploinsufficient Mice in Response to DMH—The purpose of this study was to determine the impact of BER deficiency on colon carcinogenesis in an animal model

Summary

Introduction

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, colon cancer. 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 moiety; and (v) ligation. This remains the predominant BER pathway and is clearly the pathway for repair of uracil. This study has important human health implications, as polymorphisms within the human population may render individuals haploinsufficient for ␤-pol and increase cancer risk by reducing their DNA damage tolerance

Objectives

Results

Conclusion