Publication Date
2019
Document Type
Thesis
Committee Members
Michael G. Kemp (Advisor), Jeffrey B. Travers (Committee Member), Yong-jie Xu (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Ataxia-telangiectasia and Rad-3 related (ATR) is a DNA damage response protein kinase that is upregulated in various cancer cell types and has key roles in cell cycle progression, DNA repair and apoptosis. Small molecule ATR kinase inhibitors are of importance as antineoplastic agents because they sensitize cancer cells to DNA damaging chemotherapy drugs. However, only a few studies have looked at the effects of ATR kinase inhibitors on non-replicating cells, which constitute the majority of cells in the human body and have suggested an opposite, pro-apoptotic role for ATR kinase signaling in non-replicating cells in comparison to a pro-survival function in replicating cells. Therefore, experimentations were conducted to explore this new role by using chemical inhibitors of ATR kinase in quiescent human keratinocytes in vitro and skin explants ex vivo irradiated with UVB. ATR kinase was activated in quiescent keratinocytes in DNA translocase and repair factor XPB-dependent manner whereas ATR inhibition reduced apoptotic signaling and apoptotic sunburn cells in Human skin epidermis. ATR kinase acutely protected the cells from DNA damage-induced cytotoxicity and cell death and upon cell cycle re-entry, conserves cell proliferation and limits mutagenesis at the hypoxanthine phosphoribosyltransferase locus. Loss of ATR kinase activated TLS polymerase dependent mutagenic Translesion DNA synthesis for gap filling followed by Nucleotide excision repair in quiescent keratinocytes exposed to DNA damaging UVB. In conclusion, these results indicate that the ATR kinase has a pro-proliferative role in quiescent keratinocytes whereas it has a pro-apoptotic role in human skin epidermis. It has important roles in promoting cell viability and proliferation and in preventing mutagenesis following UVB exposure even in cells that are not actively synthesizing DNA. Also, the mutagenic consequences of ATR inhibition in these cells have implications for the use of small molecule ATR kinase inhibitors in chemotherapy.
Page Count
49
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2019
Copyright
Copyright 2019, some rights reserved. My ETD may be copied and distributed only for non-commercial purposes and may not be modified. All use must give me credit as the original author.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
