Access Type

Open Access Embargo

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Steve M. Patrick

Abstract

Identifying the mechanisms mediating cisplatin response is essential for improving patient response. Previous research has identified base excision repair (BER) and mismatch repair (MMR) activity in sensitizing cells to cisplatin. Of importance, uracil DNA glycosylase (UNG) is required to initiate the BER response to cisplatin treatment and maintain drug sensitivity. Cisplatin forms DNA adducts including interstrand crosslinks (ICLs) that distort the DNA helix, forcing adjacent cytosines to become extrahelical. These extrahelical cytosines provide a substrate for cytosine deaminases. Herein, we show that APOBEC3 (A3) enzymes are capable of deaminating the extrahelical cytosines and sensitizing breast and head and neck cancer (HNSC) cells to cisplatin. The Cancer Genome Atlas (TCGA) HNSC data were used to assess the association between the expression of the seven proteins in the A3 cytosine deaminase family, HPV-status and survival outcomes. Higher A3G expression in HPV-positive tumors corresponds with better overall survival (OS). This study also used TCGA breast cancer data, Gene Expression Omnibus (GEO) datasets, and a hospital-based cohort to determined associations in A3 expression and OS in breast cancer. Breast cancer cases with high A3D, A3F, A3G or A3H expression had better OS than cases with low expression. These findings highlight a novel role of A3s in improving OS of breast cancer and HNSC patients. We demonstrate that A3, Polβ, and MSH6 knockdown in breast cancer and HNSC cells results in resistance to cisplatin and carboplatin as well as an increase in the rate of ICL removal. Knockdown of A3s results in resistance to cisplatin while induction of A3 expression using IFNα-2b in low A3 expressing cells increases sensitivity to cisplatin. We propose a novel role for A3s in activating BER through specific cytosine deamination at cisplatin ICL DNA structures. The resulting activation of BER and ultimately MMR leads to non-productive processing and blocking of ICL DNA repair which enhances cisplatin efficacy and improves patient outcomes. These studies have identified a novel role for specific A3s in mediating overall survival in breast and HNSC cancer patients and could be useful as biomarkers to inform treatment decisions.

Available for download on Wednesday, January 19, 2022

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