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Access Type

WSU Access

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

Ashok S. Bhagwat

Abstract

The AID/APOBEC family of enzymes deaminate cytosines in single-stranded DNA to uracils leading to base substitutions and strand breaks. Members of APOBEC3 family in humans are induced by cytokines produced during the body's inflammatory response to infections and provide innate immunity against viruses. However, there is emerging consensus that these enzymes can cause mutations in the cellular genome depending on the physiological state of the cell and the phase of the cell cycle they are expressed. Since aberrant expression of APOBEC3B was recently identified as a possible source of cancer, we initiated a study to determine the maximally active catalytic domain of this enzyme. The results shed light on the structural organization of APOBEC3B catalytic domain, its substrate specificity and its possible role in causing genome-wide mutations. Next we determined the effects of inflammatory stimuli on APOBEC3 expression and its consequences of genomic DNA by using a phorbol ester to induce APOBEC3A expression in a keratinocyte cell line. The inability of APOBEC3A to cause uracil accumulation in the genome was due to the reversible cessation of DNA replication and absence of single-stranded DNA substrates. We identify the reversible arrest in cell growth as an attractive mechanism to protect the human genome against APOBEC enzymes.

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