The broad long-term goal of this project is to elucidate the role of repair of endogenously modified DNA in the prevention of cancer. Our overall hypothesis is that the repair of endogenous DNA damage, including oxidized bases (Reactive Oxygen Species (ROS)-induced) and cyclic DNA adducts (enal-induced), plays a critical role in carcinogenesis. ROS and enals as such have been shown to elicit tumor promotion but detailed molecular mechanisms need to be elucidated. In this project we will use the Long Evans Cinnamon (LEG) rat as a model to investigate the mechanism. The LEG rat is genetically predisposed to spontaneous hepatocellular carcinoma (HCC). Like Wilson's disease (WD) patients, LEG rats accumulate excess copper in the liver and consequently the organ experiences severe inflammation and oxidative stress. As a result, the LEG rats develop hepatitis and the surviving animals get liver cancer. An important question is whether the chronic oxidative stress impairs repair capacity in LEG rats and as a consequence the increased oxidative damage and exocyclic adduct burden plays a critical role in HCC in LEG rat livers. Our preliminary results showed that DNA glycosylases (such as OGG1 and NTH1)-mediated excision activity of oxidized bases (8-oxoguanine and dihydrouracil) was significantly altered at different stages of HGG development in LEG rat compared to that in the control Long Evans Agouti (LEA) rat livers, and, thus prompted us to propose the following specific aims. These are to: (1) study activity and expression of repair DNA glycosylases and/or other enzymes, if found to be rate-limiting, in base excision repair (BER) pathway for repairing oxidized bases and etheno adducts in LEG and LEA rat livers, with lungs as a control; (2) study the mechanisms of regulation of NTH1 expression in LEG rat liver; (3) examine the mechanism of variation of expression and/or activity, if any, of DNA glycosylase(s) and/or other rate-limiting BER enzymes by assessing the effects of metals (copper and iron), hydrogen peroxide, and enals in hepatocytes of LEA and LEG rats and comparing the effects with that observed in tissues obtained from Aim 1; (4) study capacity to repair cyclic propano adducts (Acr-, Cro-, and HNE-dG) in LEG and LEA rat livers and lungs as control. Our preliminary results showed that HNE-dG, a major cyclic propano adduct is repaired by nucleotide excision repair (NER) pathway in mammalian cells including LEA and LEG livers. So, we will also examine the mechanism of variation, if found, of expression and/or activity of rate-limiting NER enzymes for repairing propano adducts by assessing the effects of enals in hepatocytes of LEA and LEG rats and comparing the effects with that observed in tissues. In summary, the data obtained by this project will be useful in elucidating the role of the endogenous DNA damage (oxidized bases and cyclic DNA adducts), and their repair in mutation and liver carcinogenesis. ? ? ?
| Robey, R Brooks; Weisz, Judith; Kuemmerle, Nancy B et al. (2015) Metabolic reprogramming and dysregulated metabolism: cause, consequence and/or enabler of environmental carcinogenesis? Carcinogenesis 36 Suppl 1:S203-31 |
| Langie, Sabine A S; Koppen, Gudrun; Desaulniers, Daniel et al. (2015) Causes of genome instability: the effect of low dose chemical exposures in modern society. Carcinogenesis 36 Suppl 1:S61-88 |
| Ochieng, Josiah; Nangami, Gladys N; Ogunkua, Olugbemiga et al. (2015) The impact of low-dose carcinogens and environmental disruptors on tissue invasion and metastasis. Carcinogenesis 36 Suppl 1:S128-59 |
| Woodrick, Jordan; Gupta, Suhani; Khatkar, Pooja et al. (2015) A novel method for monitoring functional lesion-specific recruitment of repair proteins in live cells. Mutat Res 775:48-58 |
| Thompson, Patricia A; Khatami, Mahin; Baglole, Carolyn J et al. (2015) Environmental immune disruptors, inflammation and cancer risk. Carcinogenesis 36 Suppl 1:S232-53 |
| Narayanan, Kannan Badri; Ali, Manaf; Barclay, Barry J et al. (2015) Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death. Carcinogenesis 36 Suppl 1:S89-110 |
| Engström, Wilhelm; Darbre, Philippa; Eriksson, Staffan et al. (2015) The potential for chemical mixtures from the environment to enable the cancer hallmark of sustained proliferative signalling. Carcinogenesis 36 Suppl 1:S38-60 |
| Kravchenko, Julia; Corsini, Emanuela; Williams, Marc A et al. (2015) Chemical compounds from anthropogenic environment and immune evasion mechanisms: potential interactions. Carcinogenesis 36 Suppl 1:S111-27 |
| Hu, Zhiwei; Brooks, Samira A; Dormoy, Valérian et al. (2015) Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis. Carcinogenesis 36 Suppl 1:S184-202 |
| Carnero, Amancio; Blanco-Aparicio, Carmen; Kondoh, Hiroshi et al. (2015) Disruptive chemicals, senescence and immortality. Carcinogenesis 36 Suppl 1:S19-37 |
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