Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) is best characterised for its involvement in DNA repair. PARP-1 activity is also linked to cell fate, confounding its roles in maintaining genome integrity. The current study assessed the functional roles of PARP-1 within human lens cells in response to oxidative stress. The human lens epithelial cell line FHL124 and whole human lens cultures were used as experimental systems. Hydrogen peroxide (H2O2) was employed to induce oxidative stress and cell death was assessed by LDH release. The functional influence of PARP-1 was assessed using targeted siRNA and chemical inhibition (by AG14361). Immunocytochemistry and western blotting were used to assess PARP-1 expression and the alkaline comet assay determined the levels of DNA strand breaks. PARP-1 was generally observed in the cell nucleus in both the FHL124 cell line and whole human lenses. PARP-1 inhibition rendered FHL124 cells more susceptible to H2O2-induced DNA strand breaks. Interestingly, reduction of PARP-1 activity significantly inhibited H2O2-induced cell death relative to control cells. Inhibition of PARP-1 in whole human lenses resulted in a reduced level of lens opacity and cell death following exposure to H2O2 relative to matched pair controls. Thus, we show that PARP-1 could play a role in the fate of human lens cells, and these first observations in human lenses suggest that it could impact on lens opacity. Further studies are required to elucidate the regulatory processes that give rise to these effects.
Highlights
Poly-ADP-ribose polymerases (PARPs) are a family of proteins that are linked with a wide-range of DNA repair pathways [1,2,3,4,5,6]
We have demonstrated that Poly(ADP-ribose) polymerase-1 (PARP-1) can influence both DNA damage and cell death in human lens cells and, PARPs could putatively affect lens maintenance and disease
In the present study we have demonstrated PARP-1 expression in the human lens cell line FHL124 and in the native human lens epithelium, and in each instance this expression was predominantly nuclear
Summary
Poly-ADP-ribose polymerases (PARPs) are a family of proteins that are linked with a wide-range of DNA repair pathways [1,2,3,4,5,6]. The human genome contains $ 150 different genes that are devoted to DNA repair processes [15,16], whose importance is underscored by the debilitating clinical symptoms that arise when these are defective [14]. The significance of the relationship between DNA damage/repair and human diseases was recognised in 2015 by the award of the Nobel Prize in Chemistry to Tomas Lindahl, Aziz Sancar, and Paul Modrich [18]. A detailed understanding of DNA repair mechanisms will provide insights into biological processes that are fundamental to improving lifelong health and wellbeing in humans
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