Journal
CELL CYCLE
Volume 14, Issue 24, Pages 3864-3876Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15384101.2015.1120914
Keywords
dNTP metabolism; erythropoiesis; erythroid development; replication stress; thymidine
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Funding
- Fundacio Bosch i Gimpera, University of Barcelona [FBG300412]
- Fundacio Bosch i Gimpera [FBG300412]
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An adequate supply of nucleotides is essential for accurate DNA replication, and inappropriate deoxyribonucleotide triphosphate (dNTP) concentrations can lead to replication stress, a common source of DNA damage, genomic instability and tumourigenesis. Here, we provide evidence that Erk5 is necessary for correct nucleotide supply during erythroid development. Mice with Erk5 knockout in the haematopoietic lineage showed impaired erythroid development in bone marrow, accompanied by altered dNTP levels and increased DNA mutagenesis in erythroid progenitors as detected by exome sequencing. Moreover, Erk5-depleted leukemic Jurkat cells presented a marked sensitivity to thymidine-induced S phase stalling, as evidenced by increased H2AX phosphorylation and apoptosis. The increase in thymidine sensitivity correlated with a higher dTTP/dCTP ratio. These results indicate that Erk5 is necessary to maintain the balance of nucleotide levels, thus preventing dNTP misincorporation and DNA damage in proliferative erythroid progenitors and leukemic Jurkat T cells.
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