SRA

Cockayne Syndrome (CS) is a rare neurodegenerative disease characterized by short stature, cachexia, sun-sensitivity, accelerated aging, and short lifespan. Mutations in two human genes, ERCC8/CSA and ERCC6/CSB, are causative for CS and the protein products of these genes, CSA and CSB, while structurally unrelated, play roles in DNA repair and other aspects of DNA metabolism in human cells. Many clinical and molecular features of CS remain poorly understood, and it has been suggested that CSA and CSB regulate transcription of rDNA genes and ribosome biogenesis. The goal of this study was to investigate the dysregulation of rRNA synthesis in CS. Here, we report that Nucleolin (Ncl), a nucleolar protein that regulates rRNA synthesis and ribosome biogenesis, interacts specifically with CSA and CSB. In addition, CSA induces ubiquitination of Ncl, enhances binding of CSB to Ncl, and CSA and CSB both stimulate binding of Ncl to rDNA and subsequent rRNA synthesis. These findings suggest that CSA and CSB are positive regulators of rRNA synthesis via Ncl regulation. A majority of CS patients carry mutations in CSA and CSB and present with similar clinical features, thus our findings may provide novel insights into disease mechanism and the neuropathological features of CS. Overall design: Examination of CSB UBD mutation expression compared to WT CSB in CS1AN cells