ZMAT3 alleviates cell death in Fanconi anemia via adaptation of sphingolipid metabolism

Abstract

Fanconi anemia (FA) is characterized by defective DNA repair and chronic p53 activation, predisposing to acute myeloid leukemia through persistent genomic instability. The molecular adaptations enabling cell survival under chronic stress remain poorly understood. This study investigates the role of ZMAT3, a p53 responsive RNA binding protein overexpressed in FA deficient cells, to elucidate its role in cellular adaptation. Using FA patient fibroblasts and Fancg KO mouse models, we launched transcriptomic profiling, lipidomic, and functional analyses. RNA-seq and lipidomic analyses revealed unexpected alterations in sphingolipid metabolism upon ZMAT3 depletion, linked to ceramide accumulation and downregulation of ASAH1 (acid ceramidase). Functionally, ZMAT3 depletion increased DNA damage and enhanced ferroptosis susceptibility, an iron dependent cell death mechanism. Mechanistically, our results showed that ZMAT3 promotes ASAH1 expression, limits ceramide accumulation and protects cells from ferroptosis induced death which could participate to preleukemic clonal evolution and pointing to areas for further exploration in FA-associated malignancies.

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Cite

BibTeX RIS

BibTeX

@article{loock2026zmat3,
  title = {{ZMAT3 alleviates cell death in Fanconi anemia via adaptation of sphingolipid metabolism}},
  author = {Maeva Loock and Blandine Lucchini and Emmanuelle Latour and Margot Tissandier and Marie Lhomme and Maharajah Ponnaiah and Lucie Hernandez and Loic Maillard and Jean Soulier and Olivier Bluteau and Camille Lobry and Marie-Laure Arcangeli and Wilfried Le Goff and Dominique Bluteau},
  journal = {Science Advances},
  year = {2026},
  month = jul,
  doi = {10.1126/sciadv.aeb6444},
  url = {https://hal.science/hal-05793781v1},
  note = {CC BY},
}

RIS

TY  - JOUR
TI  - ZMAT3 alleviates cell death in Fanconi anemia via adaptation of sphingolipid metabolism
AU  - Maeva Loock
AU  - Blandine Lucchini
AU  - Emmanuelle Latour
AU  - Margot Tissandier
AU  - Marie Lhomme
AU  - Maharajah Ponnaiah
AU  - Lucie Hernandez
AU  - Loic Maillard
AU  - Jean Soulier
AU  - Olivier Bluteau
AU  - Camille Lobry
AU  - Marie-Laure Arcangeli
AU  - Wilfried Le Goff
AU  - Dominique Bluteau
PY  - 2026
DA  - 2026/07/31
JO  - Science Advances
DO  - 10.1126/sciadv.aeb6444
UR  - https://hal.science/hal-05793781v1
AB  - Fanconi anemia (FA) is characterized by defective DNA repair and chronic p53 activation, predisposing to acute myeloid leukemia through persistent genomic instability. The molecular adaptations enabling cell survival under chronic stress remain poorly understood. This study investigates the role of ZMAT3, a p53 responsive RNA binding protein overexpressed in FA deficient cells, to elucidate its role in cellular adaptation. Using FA patient fibroblasts and Fancg KO mouse models, we launched transcriptomic profiling, lipidomic, and functional analyses. RNA-seq and lipidomic analyses revealed unexpected alterations in sphingolipid metabolism upon ZMAT3 depletion, linked to ceramide accumulation and downregulation of ASAH1 (acid ceramidase). Functionally, ZMAT3 depletion increased DNA damage and enhanced ferroptosis susceptibility, an iron dependent cell death mechanism. Mechanistically, our results showed that ZMAT3 promotes ASAH1 expression, limits ceramide accumulation and protects cells from ferroptosis induced death which could participate to preleukemic clonal evolution and pointing to areas for further exploration in FA-associated malignancies.
SN  - 2375-2548
ER  -

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