miR-29a-3p and TGF-beta Axis in Fanconi Anemia: Mechanisms Driving Metabolic Dysfunction and Genome Stability

Bertola, N.; Regis, S.; Cossu, V.; Balbi, M.; Serra, M.; Corsolini, F.; Bottino, C.; Degan, P.; Dufour, C.; Pierri, F.; Cappelli, E.; Ravera, S.

doi:10.1101/2025.01.14.632746

bioRxiv · 10.1101/2025.01.14.632746

miR-29a-3p and TGF-beta Axis in Fanconi Anemia: Mechanisms Driving Metabolic Dysfunction and Genome Stability

Bertola, N.·Regis, S.·Cossu, V.·Balbi, M.·Serra, M.·Corsolini, F.·Bottino, C.·Degan, P.·Dufour, C.·Pierri, F.·Cappelli, E.·Ravera, S.

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Abstract

Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure and cancer susceptibility due to defective DNA double-strand break repair. However, FA cells are also characterized by mitochondrial dysfunction and redox imbalance. To identify a common factor among these alterations, we focused on miR-29a-3p, a microRNA involved in hematopoiesis. Our data show that miR-29a-3p is downregulated in lymphoblasts and fibroblasts mutated for the FANC-A gene, causing the overexpression of its target genes, FOXO3, SGK1, and IGF1, which results in PI3K/AKT pathway hyperactivation, altered mitochondrial metabolism and insufficient antioxidant response. Furthermore, miR-29a-3p downregulation appears associated with hyperactivation of the TGF-{beta} signal. However, restoring miR-29a-3p expression improves mitochondrial metabolism, oxidative stress response, and DNA damage repair by inhibiting the PI3K/AKT pathway and modulating TGF-{beta} signaling by a feedback mechanism. Based on these findings, miR-29a-3p appears as a promising molecular target to address several mechanisms based on FA pathogenesis.

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Bertola, N., Regis, S., Cossu, V., Balbi, M., Serra, M., Corsolini, F., Bottino, C., Degan, P., Dufour, C., Pierri, F., Cappelli, E., Ravera, S.. 2025-01-15. miR-29a-3p and TGF-beta Axis in Fanconi Anemia: Mechanisms Driving Metabolic Dysfunction and Genome Stability. https://doi.org/10.1101/2025.01.14.632746

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