The role of the Cockayne syndrome protein

点击翻译按钮获取中文摘要

Cockayne syndrome (CS) is a devastating autosomal recessive disease characterized by neurodegeneration, cachexia, and accelerated aging. Mutations in CSA and CSB cause CS. In CS cells, there are deficiencies in the repair of oxidative DNA damage in both nuclear and mitochondrial DNA, and this may contribute to disease features. Previously, we demonstrated that the CSB protein interacts with PARP1, a protein involved in the early steps of DNA DNA damage repair, and that these two proteins cooperate in the cellular responses to oxidative stress. We also showed that there are alterations of chromatin structure in CSB-deficient cells, similar to some other premature aging models. Many clinical and molecular features of CS remain poorly understood, and it was observed that CSA and CSB regulate transcription of ribosomal DNA (rDNA) genes and ribosome biogenesis. In a recent paper, we investigated the dysregulation of rRNA synthesis in CS. We reported that Nucleolin (Ncl), a nucleolar protein that regulates rRNA synthesis and ribosome biogenesis, interacts with CSA and CSB. In addition, CSA induces ubiquitination of Ncl, and enhances binding of CSB to Ncl, and CSA and CSB both stimulate the binding of Ncl to rDNA and subsequent rRNA synthesis. CSB and CSA also increase RNA Polymerase I loading onto the coding region of the rDNA and this is Ncl dependent. These findings suggest that CSA and CSB are positive regulators of rRNA synthesis via Ncl regulation. Most CS patients carry mutations in CSA or CSB and present with similar clinical features, thus our findings provide novel insights into possible disease mechanism. In another study, described in another annual report on premature aging, one of the consistently observed features in CS patients is progressive and profound hearing loss. Thus, we initiated studies to characterize hearing defects in CS mice and continue to characterize the molecular mechanisms involved. We also identified that NAD supplementation prevents the hearing loss in CS mice.