Novel Relationships between BER Glycosylases and Mutagenic DNA Adducts

Georgetown University, Washington DC

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Abstract

Hypoxanthine (Hx) is a major DNA lesion generated by deamination of adenine during chronic inflammation, which is an underlying cause of various diseases including cancer of colon, liver, pancreas, bladder and stomach. There is evidence that deamination of DNA bases induces mutations, but no study has directly linked Hx accumulation to mutagenesis and strand-specific mutations in human cells. For the first aim, I examined the frequency, type, and distribution of mutations that result from hypoxanthine incorporation in human normal HEK293 cells, and in cancer HCT116 cells. I found that Hx is a major DNA lesion that causes large scale deletions, A:T?G:C transition mutations, insertions, and variation of mutations in the leading and lagging strands of DNA. This is the first report of direct evidence of mutagenic potential and mutation patterns of Hx in live human cells. Furthermore, I have also found that Hx, previously thought to be only repaired by N- methylpurine DNA glycosylase (MPG), is also excised by 8-oxoguanine DNA glycosylase (OGG1). For the remainder of my thesis (Aim 2) I will seek to investigate Hx?s prevalence in normal and cancerous human tissue. I will also examine OGG1?s role in the excision and repair of Hx through various biochemical characterizations. Upon completion of my PhD (Aim 3), I would like transition to a post-doctorate position investigating radiation, DNA damage, and cancer incurred during long duration spaceflight.