Folate deficiency is an important public health concern as defined by its role in the development of many health problems, including birth defects, cardiovascular disease, Alzheimer's disease and cancer. A putative role for folate in protecting from cancer is convincingly suggested in both human and animal studies. We suggest that the mechanism by which folate deficiency increases cancer risk is by reducing the ability to repair damaged DNA. This is supported by a large body of experimental evidence demonstrating an accumulation of DNA damage, which suggests that an inability to repair this damage occurs in response to folate deficiency. Our hypothesis is that the accumulation of DNA damage, preneoplastic lesions and tumors caused by folate deficiency and carcinogen exposure will be accelerated by loss of ?-pol, the rate limiting enzyme in base excision repair (BER) pathway. We have developed a BER deficient animal model that expresses a phenotype of cancer susceptibility and reduced DNA damage threshold. We propose that low levels of folate induce BER deficiency by overwhelming the pathway. In an animal model deficient in BER, the resulting damage may so overburden the pathway that BER becomes ineffectual.
The Specific Aims of this proposal are: 1) To determine the sensitivity of a BER deficient animal to folate deficiency; 2) To determine the sensitivity of a BER deficient animal to oxidative and alkylation damage when folate is deficient; 3) To evaluate whether BER deficiency accelerates the induction of preneoplastic lesions induced by DMH and 2-NP; and 4) To determine whether BER deficiency accelerates the induction of tumors caused by DMH and 2-NP when folate is deficient.
The specific aims are designed to allow us to identify the precipitating factors in the development of tumors, and the impact that folate and BER deficiency have in these processes. If we find that cancer risk is modifiable in an animal model with BER deficiency, then development of a high throughput screening tool to identify individuals with reduced BER capacity would allow caretakers to identify individuals at risk, and provide an intervention i.e., folate supplementation. ? ?
|Unnikrishnan, Archana; Prychitko, Tom M; Patel, Hiral V et al. (2011) Folate deficiency regulates expression of DNA polymerase ýý in response to oxidative stress. Free Radic Biol Med 50:270-80|
|Ventrella-Lucente, Lisa F; Unnikrishnan, Archana; Pilling, Amanda B et al. (2010) Folate deficiency provides protection against colon carcinogenesis in DNA polymerase beta haploinsufficient mice. J Biol Chem 285:19246-58|
|Unnikrishnan, Archana; Raffoul, Julian J; Patel, Hiral V et al. (2009) Oxidative stress alters base excision repair pathway and increases apoptotic response in apurinic/apyrimidinic endonuclease 1/redox factor-1 haploinsufficient mice. Free Radic Biol Med 46:1488-99|
|Heydari, Ahmad R; Unnikrishnan, Archana; Lucente, Lisa Ventrella et al. (2007) Caloric restriction and genomic stability. Nucleic Acids Res 35:7485-96|