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M. Marchetti, G.O. Pizarro, D. Sagher, C. DeAmicis, W. Lee, J.F. Hejtmancik, H. Weissbach, M. Kantorow; Three Distinct Human Lens Methionine Sulfoxide B Genes Are Important for Lens Cell Viability and Provide Distinct Levels of Oxidative Stress Resistance . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3610.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose:Methionine sulfoxide accumulation is a major feature of age related cataract that can be repaired by a unique class of enzymes called Methionine sulfoxide reductases that act on R–and S–epimers of methionine sulfoxide (MSO). MsrA acts on S–MSO while three distinct MsrBs called B1, B2 and B3 act on R–MSO. Deletion of MsrA results in loss of lifespan in mice while overexpression of MsrA provides lens and other cells resistance to oxidative stress. Here we sought to establish the range of MsrB’s expressed by the human lens and we evaluated the ability of the identified genes to confer oxidative stress resistance to human lens epithelial cells. Methods: RNA was extracted from microdissected bovine and human lenses and the enzyme activities, gene identities and spatial expression patterns of lens MsrA and MsrB genes were examined. The ability of the identified Msrs to resist oxidative stress was measured by siRNA–mediated gene silencing in conjunction with TBHP treatment and viability measurements in human SRA0411 lens cells. Corresponding levels of apoptosis were detected using TUNEL labeling. Results: Approximately 40% of the Msr activity in human lens epithelium and fibers is contributed by MsrB. Three separate MsrB genes are expressed by the human lens including MsrB1 (Selenoprotein R), MsrB2 (CBS–1) and MsrB3. These genes are variably expressed in different human tissues and lens sub–locations. Interestingly all the identified MsrBs are required for lens cell viability even in the absence of exogenous oxidative stress. MsrA and B2 are known to localize to the mitochondria and these Msrs but not B1 or B3 confer oxidative stress resistance to lens cells. Conclusions: These data demonstrate that the human lens contains both MsrA and MsrB activity and expresses MsrA, MsrB1, MsrB2 and MsrB3 genes. The varied expression of these genes in different tissues and lens sub–locations together with evidence for different activities of the proteins in providing resistance to oxidative stress suggest specialized roles for these genes in lens function, including resistance to oxidative stress and potentially to cataract formation.
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