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Matina Economopoulou, Ria Zengler, Lutz E Pillunat, Andre Nussenzweig, Triantafyllos Chavakis; The role of 53bp1 and of the endothelial DNA repair cascade in the vasoprolifarative retinopathies. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3017.
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© ARVO (1962-2015); The Authors (2016-present)
Hypoxia is central in the vasoprolifearative retinopathies (DR, ROP) as it is the driving force for the endothelial cell (EC) proliferation. On the other hand hypoxia and reoxygeneation lead to stalled replication forks and activation the DNA repair machinery leading to replication arrest and apoptosis. The DNA is repaired either by homologous recombination (HR) or non homologous end-joining (NHEJ). During the S Phase of the cell cycle, HR is the main mode of DNA repair. p53 binding protein1 (53bp1) is a DNA repair factor that promotes NHEJ and competes with BRCA1 (that promotes HR) for the DNA repair mode. Given our previous finding that H2Ax and endothelial DNA repair are critical for hypoxia-driven angiogenesis in retinopathy (Economopoulou et al., Nat Med 2009), we here explored the role of 53bp1 in ROP.
We subjected ECs to hypoxia/ reoxygenation (H/Reox) conditions and studied the phosphorylation of 53bp1 (p-53bp1) by IF and WB. In vivo we subjected 53bp1-/- and +/+ mice to the ROP model. Their retinas were analysed for neovascularisation, EC proliferation and apoptosis and WB quantification of the DNA repair factors BRCA1 and Rad51.
The exposure of ECs to H/Reox conditions resulted in an increase in p-53bp1. Furthermore, H/Reox upregulated other DNA repair factors, mostly involved in HR, like RAD51. The retinas of 53bp1-/- ROP mice showed significantly higher neovascularisation compared to their wt littermates. This was due to higher EC proliferation and lower apoptosis in the retinas of 53bp1-/- mice. Furthermore BRCA1 and Rad51 were significanty upregulated in the retinas of 53bp1-/- ROP mice compared to 53bp1+/+ suggesting a higher rate of HR in the 53bp1-/- retinas.
Our study shows a novel role of 53bp1 in vasoproliferative retinopathies. The absence of 53bp1 results in increased neovascularisation due to enhanced EC proliferation and decreased apoptosis in the retinas of ROP mice. We propose that the increase in BRCA1 and Rad51 in the retinas of 53bp1-/- mice lead to a more efficient EC proliferation under H/Reox conditions in the ischemic retina. Intriguingly, our results show an opposite role of 53bp1 to the function of histone H2AX in the ROP. Overall, our study strengthens the notion that the DNA Repair cascade is important in vasoproliferative retinopathies and identifies the variable effects of different DNA repair proteins in this context.
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