Oregon Health & Science University
Hepatocellular carcinoma (HCC) is a serious global public health issue. With 782,000 new cases diagnosed in 2012, HCC is the second leading cause of death related to cancer worldwide. The majority of HCC cases occur in developing countries in Southeast Asia, Sub-Saharan Africa and China. Hepatitis B virus (HBV) infection and aflatoxin exposure are the two main factors contributing to HCC in these high incidence regions. While HBV vaccination provides an effective way to lower the risk of HCC, there are an estimated 5 billion people at risk of chronic exposure to aflatoxins through contaminated food. To develop effective treatment, early diagnosis, and intervention strategies, a better understanding of the mechanisms by which aflatoxins induce HCC is paramount. Aflatoxin B1 (AFB1) is the most potent hepatocarcinogen among the aflatoxins. The first chapter of this dissertation provides a review of the mechanism of action of AFB1 in hepatocarcinogenesis, with a focus on the differential susceptibilities between species and individuals, and highlights unanswered questions that await further investigation. Upon exposure to AFB1, DNA damage and mutations have been observed. Genetic alterations are considered to be the initial step of tumor development, but how AFB1-induced DNA lesions result in mutations remains unclear. To address this question, the aim of the second and third chapters of this dissertation is to determine the mutagenic potential of the primary and secondary AFB1-DNA adducts in primate cells. The biochemical function of a subset of eukaryotic translesion synthesis (TLS) DNA polymerases, whose DNA damage tolerance mechanism carries a risk of mutagenesis, is also explored with regard to replication bypass of AFB1-DNA adducts. To extend these studies, the aim of chapter four of the dissertation is to narrowly focus on elucidating the biological role of pol ζ in response to AFB1. Cells have evolved a variety of DNA repair pathways to prevent mutation and genome instability. One key observation regarding AFB1-induced genotoxicity is that the secondary AFB1-DNA adducts appear to accumulate in mammalian cells for several days after a single dose of AFB1 exposure, raising the question of how these adducts are repaired in mammalian cells. In this regard, the aim of chapter five of this dissertation is to evaluate the catalytic efficiency of human DNA glycosylase Nei endonuclease VIII-like 1 (hNEIL1) in excision of the secondary AFB1-DNA adducts in order to determine the involvement of base excision repair (BER) for combating AFB1- induced genotoxicity. Overall, the results presented in this dissertation advance our state of knowledge about the mechanism of AFB1-induced mutagenesis in mammalian cells through the function of TLS pol ζ, and how BER may modulate the genotoxic and mutagenic outcomes.
Cell, Development & Cancer Biology Program
School of Medicine
Lin, Ying-Chih, "Mechanism of aflatoxin-induced mutagenesis" (2015). Scholar Archive. 3607.
Available for download on Sunday, March 18, 2018