Effect Of Dietary Folate Restriction On Colon Carcinogenesis In Dna Polymerase β Haploinsufficient Mice

<p>The data presented in this research is central to establishing the role that the base excision repair pathway (BER) plays in the development and progression of colon cancer when dietary folate is deficient. Both cellular folate restriction and BER deficiencies have been shown to result in the accumulation of endogenous damage and lesions that could eventually develop into carcinogenesis. In this study, a dietary folate deficiency (FD) resulted in a significant increase in aberrant crypt foci (ACF) formation and triggered liver tumorogenesis in wildtype (WT) animals, as did a BER deficiency in DNA polymerase Β haploinsufficient (Β-pol+/-) mice exposed to 1, 2-dimethylhydrazine (DMH), a known colon and liver carcinogen. We combined both folate restriction and a BER deficiency to determine the fate of colon tissue after exposure to DMH. Of interest, we show that this model supports a protection against colon carcinogenesis. FD attenuated onset and progression of ACF and prevented liver tumorigenesis in Β-pol haploinsufficient mice. Analysis of the data suggests that the mechanism by which this phenomenon occurs appears to be through an elevation in DNA damage that signals recruitment of PARP enzymes to the site of damage, however, with a deficiency in BER, PARP function in DNA repair is futile leading to a depletion of cellular energetic levels. This energetic stress is sensed by cell death machinery and as such apoptosis is invoked.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Open Access Dissertation

Discipline thesis:degree_discipline

Nutrition and Food Science

Year dc:date.available

2010

Author dc:creator

• Ventrella Lucente, Lisa F.

Contributors dc:contributor

• Ahmad R. Heydari

• base excison repair
• colon cancer
• DNA polymerase beta
• folate deficiency
• Medical Molecular Biology
• Molecular, Genetic, and Biochemical Nutrition
• Nutrition

Repository record dc:identifier

https://digitalcommons.wayne.edu/oa_dissertations/54

OAI identifier oai:identifier

oai:digitalcommons.wayne.edu:oa_dissertations-1053