The role of the Cockayne syndrome protein

Cockayne综合征(CS)是一种以神经变性、恶病质和加速衰老为特征的常染色体隐性遗传病。CsA和CSB的突变会导致CS。在CS细胞中，核和线粒体DNA氧化损伤的修复都存在缺陷，这可能与疾病的特征有关。在此之前，我们证明了CSB蛋白与PARP1蛋白相互作用，PARP1蛋白参与DNA DNA损伤修复的早期步骤，这两种蛋白在细胞对氧化应激的反应中相互作用。我们还发现，在CSB缺陷的细胞中存在染色质结构的变化，类似于其他一些早衰模型。 CS的许多临床和分子特征尚不清楚，已观察到CsA和CSB调节核糖体DNA(RDNA)基因的转录和核糖体的生物发生。在最近的一篇论文中，我们研究了CS中rRNA合成的失调。我们报道了核仁蛋白(NCL)与CsA和CSB相互作用，NCL是一种调节rRNA合成和核糖体生物发生的核仁蛋白。此外，CsA可诱导NCL的泛素化，并增强CSB与NCL的结合，CsA和CSB均可刺激NCL与rDNA的结合以及随后的rRNA合成。CSB和CsA还增加了RNA聚合酶I在rDNA编码区的载量，这是NCL依赖的。这些结果表明，CsA和CSB是通过NCL调节rRNA合成的正调控因子。大多数CS患者携带CsA或CSB突变，并具有相似的临床特征，因此我们的发现为 可能的致病机制。 在另一份关于过早衰老的年度报告中描述的另一项研究中，CS患者持续观察到的特征之一是进行性和严重的听力损失。因此，我们开始研究CS小鼠的听力缺陷，并继续研究其中的分子机制。我们还发现NAD补充剂可以预防CS小鼠的听力损失。

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.