Genotoxicity of tetrahydrofolic acid to hematopoietic stem and progenitor cells

• Published in: Cell death and differentiation Vol. 25; no. 11; pp. 1967 - 1979
• Main Authors: García-Calderón, Clara B., Bejarano-García, José Antonio, Tinoco-Gago, Isabel, Castro, María José, Moreno-Gordillo, Paula, Piruat, José I., Caballero-Velázquez, Teresa, Pérez-Simón, José A., Rosado, Iván V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2018; Nature Publishing Group
• Subjects: 13/100; 14; 14/1; 14/63; 59; 631/337; 631/67/2327; 64; 64/60; 82; 96; 96/31; Apoptosis; Biochemistry; Biomedical and Life Sciences; Bone marrow; Cell Biology; Cell Cycle Analysis; Cytotoxicity; DNA damage; DNA repair; Fanconi syndrome; Formaldehyde; Genomes; Genomic instability; Genotoxicity; Hematological diseases; Hematopoietic stem cells; Life Sciences; Progenitor cells; Replication forks; Stem Cells; Tetrahydrofolic acid; Thymidylate synthase
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-018-0089-4

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.