DNA Based Repair and MAP kinases

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DESCRIPTION (provided by applicant): Endogenous and environmental oxidation can cause DMA damage along with other organelle injury. For example, hyperoxia is a main therapeutics for acute lung failure but also causes lung cell toxicity. Since treatment of hyperoxic toxicity and other oxidation is largely supportive and natural defense mechanisms are easily defeated, development of new therapeutic strategies is warranted. Our preliminary data indicates that hyperoxia induces apoptosis associated with activation of mitogen-activated protein kinases (MARK, p38 and ERK1/2). We have also found that DNA base excision repair (BER) proteins can reverse oxidative DMA damage. However, it is unclear whether BER proteins interact with signaling proteins such as MARK. The objective of this application is to determine roles of BER in hyperoxic DNA damage and the regulatory mechanism, particularly interactions of BER proteins with MARK. Our central hypothesis is that BER proteins may regulate or interact with the MARK pathway to reverse DNA damage. Hyperoxia injured cells must either cease replication due to cell cycle arrest or replicate with a mutant form of DNA. Thus, DNA repair is urgently needed. Failure to repair the DNA damage results in genetic disintegration, apoptotic cell death, and an ultimate alveolar breakdown. MARK may help efficiently repair DNA damage, thus a critical way to reduce oxidative toxicity. The rationale is that additional knowledge of BER interacting with other signaling proteins would provide a foundation to better use BER DNA repair proteins to prevent oxidative injury. To test our hypothesis, we propose the following Specific Aims: #1 To identify hyperoxia-induced DNA lesions and alterations of MARK activity; #2 To evaluate role of BER proteins in regulating MARK activity. The significance is that regulation of BER repair and signaling proteins may be potentially useful for counteracting various oxidative damage to lung cells, including chemotherapeutics and heavy metals, such as cadmium.