PhD (Doctor of Philosophy)
Date of Award
Committee Chair or Co-Chairs
Chuanfu Li, Phil Musich, Victoria Palau, Antonio Rusinol, Charles Stuart
From gametogenesis until death an organism’s genome is under constant bombardment from endogenous and exogenous sources of DNA damage. To maintain genomic integrity amid this damage, cells have evolved responses which allow them to either preserve viability for recovery or initiate self-destructive pathways depending on the severity of DNA damage. One protein involved in initiating and carrying out these responses is the protein kinase ataxia telangiectasia and Rad3-related (ATR). ATR is known primarily for its regulatory role in initiating the checkpoint-signaling cascade following DNA damage and replicative stress. These signaling events lead to cell cycle arrest, DNA repair, or apoptosis when damage is too extreme. In addition to these kinase-dependent roles, ATR also is capable of directly blocking the intrinsic apoptotic pathway through structural sequestration of the proapoptotic protein tBid. The sum of these regulatory events is a delicate balancing act resulting in either cell death or cell survival depending on the severity of the damage and the differentiation state of the cell in question. In the following studies, we sought to investigate the complex interplay of ATR’s kinase and structural roles in determining cellular fate. First, we investigated the structural role of prolyl isomerization of ATR across development by using mouse models of two isomerically locked forms of ATR which were previously shown to lock cytoplasmic ATR into a single isomer. Studies showed that ATR which is locked in ATR-L (trans-ATR, hATR-P429A/mATR-P432A) is embryonically lethal and that heterozygotes tend to have neurological and other developmental abnormalities. This contrasts with ATR-H (cis-ATR, hATR-S428A/mATR-S431A), which is viable, but naturally prone to cancer development. Next, we used various in vitro stroke-like conditions to test if ATR inhibition could serve as a therapeutic target for stroke. We found that ATR inhibition is protective in non-dividing neuron-like cells; whereas, it potentiates death in cycling glial and immune-like cycling cells. Thus, ATR inhibition could likely be a target for both neuron sparing and immunosuppressive anti-stroke therapeutic strategies. Taken together, these studies provide insightful information into the structural and pathological roles of ATR in development and disease.
Dissertation - Withheld
Cartwright, Brian, "Exploration of Ataxia Telangiectasia and Rad3-Related’s (ATR’s) Role in Cell Death Regulation: Implications in Development, Cancer, and Stroke" (2019). Electronic Theses and Dissertations. Paper 3664. https://dc.etsu.edu/etd/3664
Copyright by the authors.
Available for download on Friday, November 10, 2023