Department of Genetics, Yale School of Medicine, New Haven, CT 06520.
Department of Molecular Biophysics and Biochemistry, Yale School of Medicine, New Haven, CT 06520.
Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2561-2570. doi: 10.1073/pnas.1811557116. Epub 2019 Jan 28.
Fanconi anemia (FA) is a disease of DNA repair characterized by bone marrow failure and a reduced ability to remove DNA interstrand cross-links. Here, we provide evidence that the FA protein FANCI also functions in ribosome biogenesis, the process of making ribosomes that initiates in the nucleolus. We show that FANCI localizes to the nucleolus and is functionally and physically tied to the transcription of pre-ribosomal RNA (pre-rRNA) and to large ribosomal subunit (LSU) pre-rRNA processing independent of FANCD2. While FANCI is known to be monoubiquitinated when activated for DNA repair, we find that it is predominantly in the deubiquitinated state in the nucleolus, requiring the nucleoplasmic deubiquitinase (DUB) USP1 and the nucleolar DUB USP36. Our model suggests a possible dual pathophysiology for FA that includes defects in DNA repair and in ribosome biogenesis.
范可尼贫血症（FA）是一种 DNA 修复疾病，其特征是骨髓衰竭和去除 DNA 链间交联的能力降低。在这里，我们提供的证据表明，FA 蛋白 FANCI 也在核糖体生物发生中发挥作用，核糖体生物发生是在核仁中起始的核糖体制造过程。我们表明 FANCI 定位于核仁，并且与转录前核糖体 RNA（pre-rRNA）和与 FANCD2 无关的大核糖体亚基（LSU）pre-rRNA 加工的功能和物理结合。虽然已知 FANCI 在 DNA 修复激活时被单泛素化，但我们发现它在核仁中主要处于去泛素化状态，需要核质去泛素酶（DUB）USP1 和核仁 DUB USP36。我们的模型提出了 FA 的一种可能的双重病理生理学，包括 DNA 修复和核糖体生物发生的缺陷。
