Cockayne Syndrome (CS) is a rare neurodegenerative disease characterized by short stature, accelerated aging and short lifespan. Mutations in two human genes, ERCC8/CSA and ERCC6/CSB, are causative for CS and their protein products, 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 was observed that CSA and CSB regulate transcription of ribosomal DNA (rDNA) genes and ribosome biogenesis. Here, we investigate the dysregulation of rRNA synthesis in CS. We report 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, 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 to 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 and CSB and present with similar clinical features, thus our findings provide novel insights into disease mechanism.

中文翻译：

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Cockayne 综合征 A 组和 B 组蛋白通过核仁素调节在 rRNA 转录中发挥作用。


科凯恩综合症（CS）是一种罕见的神经退行性疾病，其特征是身材矮小、加速衰老和寿命短。两个人类基因 ERCC8/CSA 和 ERCC6/CSB 的突变是 CS 及其蛋白质产物 CSA 和 CSB 的原因，虽然在结构上不相关，但在人类细胞中的 DNA 修复和 DNA 代谢的其他方面发挥着作用。 CS 的许多临床和分子特征仍知之甚少，据观察，CSA 和 CSB 调节核糖体 DNA (rDNA) 基因的转录和核糖体生物发生。在这里，我们研究了 CS 中 rRNA 合成的失调。我们报道核仁蛋白 (Ncl) 是一种调节 rRNA 合成和核糖体生物发生的核仁蛋白，与 CSA 和 CSB 相互作用。此外，CSA诱导Ncl泛素化，增强CSB与Ncl的结合，并且CSA和CSB均刺激Ncl与rDNA的结合以及随后的rRNA合成。 CSB 和 CSA 还会增加 rDNA 编码区的 RNA 聚合酶 I 负载，这是 Ncl 依赖性的。这些发现表明，CSA 和 CSB 通过 Ncl 调节而成为 rRNA 合成的正调节因子。大多数CS患者携带CSA和CSB突变，并表现出相似的临床特征，因此我们的研究结果为疾病机制提供了新的见解。