1. Fanconi anemia A protein participates in nucleolar homeostasis maintenance and ribosome biogenesis
- Author
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Guillaume Rouvet, Jean-Jacques Diaz, Frédérique Maczkowiak-Chartois, Sylvie Souquere-Besse, Sébastien Apcher, Anna Gueiderikh, Filippo Rosselli, Intégrité du génome et cancers (IGC), and Institut Gustave Roussy (IGR)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)
- Subjects
NPM1 ,congenital, hereditary, and neonatal diseases and abnormalities ,DNA repair ,DNA damage ,[SDV]Life Sciences [q-bio] ,Ribosome biogenesis ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Fanconi anemia ,hemic and lymphatic diseases ,medicine ,Homeostasis ,Humans ,ComputingMilieux_MISCELLANEOUS ,Research Articles ,030304 developmental biology ,0303 health sciences ,Nucleophosmin ,Multidisciplinary ,Fanconi Anemia Complementation Group A Protein ,Nuclear Proteins ,nutritional and metabolic diseases ,SciAdv r-articles ,Human Genetics ,Cell Biology ,medicine.disease ,FANCA ,Cell biology ,Fanconi Anemia ,030220 oncology & carcinogenesis ,Ribosomes ,Nucleolin ,Cell Nucleolus ,Research Article - Abstract
FANCA is a multitasking protein with essential functions beyond DNA repair in nucleolar homeostasis and ribosome biogenesis., Fanconi anemia (FA), the most common inherited bone marrow failure and leukemia predisposition syndrome, is generally attributed to alterations in DNA damage responses due to the loss of function of the DNA repair and replication rescue activities of the FANC pathway. Here, we report that FANCA deficiency, whose inactivation has been identified in two-thirds of FA patients, is associated with nucleolar homeostasis loss, mislocalization of key nucleolar proteins, including nucleolin (NCL) and nucleophosmin 1 (NPM1), as well as alterations in ribosome biogenesis and protein synthesis. FANCA coimmunoprecipitates with NCL and NPM1 in a FANCcore complex–independent manner and, unique among the FANCcore complex proteins, associates with ribosomal subunits, influencing the stoichiometry of the translational machineries. In conclusion, we have identified unexpected nucleolar and translational consequences specifically associated with FANCA deficiency that appears to be involved in both DNA damage and nucleolar stress responses, challenging current hypothesis on FA physiopathology.
- Published
- 2021