Back to Search
Start Over
Genotoxicity of tetrahydrofolic acid to hematopoietic stem and progenitor cells
- Source :
- Cell Death & Differentiation. 25:1967-1979
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Genome instability
DNA Repair
DNA repair
DNA damage
Apoptosis
Article
Genomic Instability
Cell Line
Histones
Mice
03 medical and health sciences
chemistry.chemical_compound
Fanconi anemia
medicine
Animals
Phosphorylation
Progenitor cell
Tetrahydrofolic acid
Molecular Biology
Tetrahydrofolates
Mice, Knockout
Chemistry
Alcohol Dehydrogenase
Hematopoietic stem cell
Thymidylate Synthase
Cell Biology
Hematopoietic Stem Cells
medicine.disease
Fanconi Anemia Complementation Group Proteins
Hematopoiesis
Cell biology
Mice, Inbred C57BL
Haematopoiesis
030104 developmental biology
medicine.anatomical_structure
Chickens
DNA Damage
Subjects
Details
- ISSN :
- 14765403 and 13509047
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Cell Death & Differentiation
- Accession number :
- edsair.doi.dedup.....e4515c70872cbb6fb082c383b264f9f7