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. 2013 Jul 26;5(3):943-58.
doi: 10.3390/cancers5030943.

PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

Amanda F Swindall  1 , Jennifer A Stanley, Eddy S Yang
Affiliations

PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

Amanda F Swindall et al. Cancers (Basel). .

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.

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Figures

Figure 1
Figure 1
Schematic delineating the multifaceted nature of Poly(ADP) Ribose Polymerase (PARP): DNA repair, Chromatin Modification, Inflammation, Transcriptional Regulation, and Cell Death.
Figure 2
Figure 2
Potential role of elevated PARP-1 in tumorigenesis. After DNA damage, PARP-1 activates DNA repair. However, PARP-1 also acts a co-activator of NFkB signaling, which can propogate inflammatory signaling and lead to more DNA damage, including the formation of oxidatively-clustered DNA lesions (OCDLs). The formation of OCDLs have been shown to be elevated in numerous tumor types. PARP-1 activity could potentially be beneficial or harmful in the repair of ROS-induced DNA lesions.
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