miR-29a-3p and TGF-β Axis in Fanconi anemia: mechanisms driving metabolic dysfunction and genome stability

miR-29a-3p and TGF-β Axis in Fanconi anemia: mechanisms driving metabolic dysfunction and genome stability

Abstract Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and cancer predisposition. The FA cellular phenotype is marked by a defective DNA double-strand break repair. Alongside this defect, FA cells exhibit mitochondrial dysfunction and redox unbalance. In addition, FA...

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Main Authors: Nadia Bertola, Stefano Regis, Vanessa Cossu, Matilde Balbi, Martina Serra, Fabio Corsolini, Cristina Bottino, Paolo Degan, Carlo Dufour, Filomena Pierri, Enrico Cappelli, Silvia Ravera
Format: Article
Language:English
Published: Springer 2025-06-01
Series:Cellular and Molecular Life Sciences
Subjects:
DNA repair
Fanconi anemia
Inflammation
MiR-29a-3p
Mitochondrial metabolism
Online Access:https://doi.org/10.1007/s00018-025-05775-w
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Summary:Abstract Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure and cancer predisposition. The FA cellular phenotype is marked by a defective DNA double-strand break repair. Alongside this defect, FA cells exhibit mitochondrial dysfunction and redox unbalance. In addition, FA cells display an altered microRNA profile, including miR-29a-3p, which plays a crucial role in hematopoiesis by supporting the self-renewal, lineage commitment, and differentiation of hematopoietic stem cells (HSCs). In this study, we demonstrate that miR-29a-3p is downregulated in lymphoblasts and fibroblasts mutated for the FANC-A gene, leading to hyperactivation of PI3K/AKT pathway due to the overexpression of its target genes, FOXO3, SGK1, and IGF1, and resulting in altered mitochondrial metabolism and insufficient antioxidant response. In addition, miR-29a-3p downregulation appears associated with hyperactivation of the TGF-β signal. By contrast, FA cells transfected with miR-29a-3p show an improvement in mitochondrial metabolism, oxidative stress response, and DNA damage accumulation, by inhibiting the PI3K/AKT pathway and modulating the TGF-β pathway through a feedback mechanism. In conclusion, our results highlight the central role of miR-29a-3p in FA cells, suggesting that it is a promising molecular target to address several mechanisms based on FA pathogenesis. Graphical abstract
ISSN:1420-9071

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