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Fanconi anemia protein FANCI functions in ribosome biogenesis

Significance FANCI is a Fanconi anemia (FA) protein and functions in DNA interstrand cross-link repair. Surprisingly, in addition to DNA repair proteins, we find that FANCI interacts with proteins that function in ribosome biogenesis, the synthesis of ribosomes in cells. Furthermore, FANCI localizes to the nucleolus—the cellular compartment in which ribosome biogenesis initiates—and functions in the transcription and processing of pre-ribosomal RNA (pre-rRNA). Interestingly, defects in ribosome biogenesis underlie three other bone marrow failure syndromes, raising the question, Do defects in ribosome biogenesis contribute to FA pathogenesis? Our results expand the functions of FANCI to encompass ribosome biogenesis and DNA repair, highlighting the importance of future investigations into the role of other FA proteins in synthesizing ribosomes. 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.