Inactivation of the SMN Complex by Oxidative Stress

Howard Hughes Medical Institute, Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6148, USA.
Molecular cell (Impact Factor: 14.02). 07/2008; 31(2):244-54. DOI: 10.1016/j.molcel.2008.06.004
Source: PubMed


The SMN complex is essential for the biogenesis of small nuclear ribonucleoproteins (snRNPs), the major constituents of the spliceosome. Deficiency in functional SMN protein causes spinal muscular atrophy, a common motor neuron degenerative disease of severity commensurate with SMN levels and, correspondingly, snRNP assembly decreases. We developed a high-throughput screen for snRNP assembly modifiers and discovered that reactive oxygen species (ROS) inhibit SMN-complex activity in a dose-dependent manner. ROS-generating compounds, e.g., the environmental toxins menadione and beta-lapachone (in vivo IC(50) = 0.45 muM) also cause intermolecular disulfide crosslinking of SMN. Both the oxidative inactivation and SMN crosslinking can be reversed by reductants. We identified two cysteines that form SMN-SMN disulfide crosslinks, defining specific contact points in oligomeric SMN. Thus, the SMN complex is a redox-sensitive assemblyosome and an ROS target, suggesting that it may play a role in oxidative stress pathophysiology, which is associated with many degenerative diseases.

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Available from: Elizabeth Ottinger, Feb 03, 2014
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    • "Their data indicate that SMN knockdown alone is not critical to cell viability. However, when SMN knockdown cells are under stress, such as oxidative stress [48], their survival rate may significantly decrease [47]. In parallel, SOD3 (extracellular superoxide dismutase, EC-SOD) was shown to be the predominant form in extracellular fluids. "
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