Abstract
Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation.
Highlights
Human tissues are exposed to various sources of reactive oxygen species, which can lead to DNA damage including single strand breaks (SSBs) and the more severe, double strand breaks (DSBs).Reactive oxygen species (ROS) are oxygen derivatives that are highly volatile toward cellular components
Cells have adapted elaborate processes to address DNA lesions caused by ROS, and these lesions are usually fixed by base excision repair (BER) and nucleotide excision repair (NER) pathways upon activation of cell cycle checkpoints [3]
Is chronic activation of PARP-1 in highly oxidative environments responsible for the increased inflammation leading to genome instability and cancer, or are the DNA damages causing an upregulation of PARP-1? One potential mechanism through which PARP-1 and the inflammation-DNA damage feedback loop could be propagated is through the development and attempted repair of oxidative clustered DNA lesions
Summary
Human tissues are exposed to various sources of reactive oxygen species, which can lead to DNA damage including single strand breaks (SSBs) and the more severe, double strand breaks (DSBs). Cellular homeostasis depends on a delicate balance between damage versus the repair of ROS-induced lesions that occur in lipids, proteins, and DNA. While cellular processes allow for the turnover of lipids and proteins damaged by interaction with ROS, DNA is non-recyclable, and DNA damages must be repaired. Continued activation of PARP-1, especially in situations of chronic inflammation/oxidation, may contribute to the formation of OCDLs and enhance tumorigenesis. Given these two diverging roles of PARP-1, the PARP inhibitors may be used to treat cancers and to prevent cancers that form from the potentiation of inflammation/ROS-induced damage caused by persistent PARP-1 upregulation in response to DNA damage. We will discuss the possibility of using PARP inhibitors in the treatment of familial cancers, and as part of a combination therapy or preventative reagent in non-familial cancers, and potentially in inflammatory diseases which carry a high risk for cancer development
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