RT Journal Article
T1 Genotoxicity of tetrahydrofolic acid to hematopoietic stem and progenitor cells.
A1 Garcia-Calderon, Clara B
A1 Bejarano-Garcia, Jose Antonio
A1 Tinoco-Gago, Isabel
A1 Castro, Maria Jose
A1 Moreno-Gordillo, Paula
A1 Piruat, Jose I
A1 Caballero-Velazquez, Teresa
A1 Perez-Simon, Jose A
A1 Rosado, Ivan V
K1 Alcohol Dehydrogenase
K1 Apoptosis
K1 Chickens
K1 Genomic Instability
K1 Histones
AB Metabolically reactive formaldehyde is a genotoxin and a carcinogen. Mice lacking the main formaldehyde-detoxifying gene Adh5 combined with the loss of the Fanconi anemia (FA) DNA repair pathway rapidly succumbed to bone marrow failure (BMF) primarily due to the extensive ablation of the hematopoietic stem cell (HSC) pool. However, the mechanism by which formaldehyde mediates these toxic effects is still unknown. We uncover a detrimental role of tetrahydrofolic acid (THF) in cells lacking Adh5 or the FA repair pathway. We show that Adh5- or FA-deficient cells are hypersensitive to formaldehyde and to THF, presenting DNA damage and genome instability. THF cytotoxicity involved imbalance of the nucleotide pool by deregulation of the thymidylate synthase (TYMS) enzyme, which stalled replication forks. In mice, THF exposure had widespread effects on hematopoiesis, affecting the frequency and the viability of myeloid- and lymphoid-committed precursor cells. Moreover, the hematopoietic stem and progenitor cells (HSPC) showed genomic instability, reduced colony-forming capacity and increased frequency of cycling and apoptotic HSCs upon THF exposure. Overall, our data reveal that the physiological pool of THF and formaldehyde challenge the stability of the genome of HSPCs that might lead to blood disorders.
PB Nature Publishing Group
YR 2018
FD 2018-11
LK http://hdl.handle.net/10668/12214
UL http://hdl.handle.net/10668/12214
LA en
NO García-Calderón CB, Bejarano-García JA, Tinoco-Gago I, Castro MJ, Moreno-Gordillo P, Piruat JI, et al. Genotoxicity of tetrahydrofolic acid to hematopoietic stem and progenitor cells. Cell Death Differ. 2018 Nov;25(11):1967-1979.
DS RISalud
RD Aug 31, 2025