Dynamics of Fanconi anemia protein D2 in association with nuclear lipid droplet formation

Abstract

Fanconi anemia is a rare genetic disease caused by the loss of function of one of the 23 associated genes and is characterized by bone marrow failure, cancer predisposition and developmental defects. The proteins encoded by these genes (FANC proteins) mainly function in DNA damage response and repair. Although FANC deficiency has multiple effects on the regulation of lipid metabolism, the molecular function of FANC proteins in the context of Fanconi anemia pathology remains unclear. In the present study, we demonstrate that FANCD2, a key component of FANC proteins, interacts with factors involved in fatty acid biosynthesis or sphingolipid metabolism and that FANCD2 deficiency downregulates the cellular levels of fatty acids. Moreover, a portion of FANCD2 is localized to nuclear lipid droplets in response to oleic acid (OA) treatment. These subcellular dynamics are independent of FANCD2 monoubiquitylation, which is essential for the DNA damage response. Collectively, these findings demonstrate that FANCD2 responds to not only DNA damage but also OA exposure, providing insights into the pathogenesis of lipid dysregulation in Fanconi anemia.