The Ubiquitin-Proteasome System and DNA Repair

Abstract

The 2004 Nobel Prize in Chemistry was awarded to Aaron Ciechanover, Avram Hershko, and Irwin Rose for their work in discovering the ubiquitin-proteasome system (UPS), as reviewed by Herrmann and others (Herrmann et al., 2007). The mechanisms by which proteolysis occurs had remained elusive until the late 1970s, when a series of key experiments paved the way for a new area of research (Ciechanover et al., 1978; Ciechanover et al., 1980b; Hershko et al., 1980). These studies revealed that the majority of protein degradation is nonlysosomal and adenosine triphosphate (ATP)-dependent. Most importantly, it was also demonstrated that this proteolysis requires at least two components: one with protease activity and another in the form of an 8.5-kDa heat-stable protein. These elements were later identified as the proteasome and ubiquitin, respectively (Ciechanover et al., 1980a; Wilkinson et al., 1980; Hough et al., 1986; Waxman et al., 1987; Arrigo et al., 1988). Substrates of the UPS include many short-lived regulatory proteins in addition to misfolded and defective proteins (Dahlmann, 2007; Naiki & Nagai, 2009; Xie, 2010). Conserved from Archaea to humans, the UPS is thought to be responsible for degrading approximately 90% of nuclear and cytoplasmic proteins (Magill et al., 2003). Through regulation of protein expression, the UPS controls processes such as protein homeostasis, cell-cycle, cell division, cellular differentiation, apoptosis, signal transduction, gene expression, immunity, and DNA repair (Magill et al., 2003; Finley, 2009; Liggett et al., 2010; Shabek & Ciechanover, 2010; Xie, 2010). Although much focus on this system revolves around its proteolytic function and regulation, members of the UPS also play non-proteolytic roles in transcription, membrane trafficking, protein kinase activation, chromatin dynamics, and DNA repair (Chen & Sun, 2009; Xie, 2010). The UPS plays one of the central roles in pathology and disease, and it has become the target of several newer therapeutic modalities. In patients with some forms of cardiac dysfunction, neurodegeneration, autoimmune disease, and viral infections, proteasome activity and/or expression is diminished (Magill et al., 2003; Dahlmann, 2007; Naiki & Nagai, 2009). Conversely, in some cancer patients and patients with cachexia, an increase in proteasome expression has been observed. According to the idea that this increase in proteosome activity is a potential therapeutic target, proteosome inhibitors are developed and isolated from natural products (Orlowski & Kuhn, 2008; Groll et al., 2009; Huang & Chen, 2009).