Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis

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 necessar...

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Bibliographic Details
Published in:Cell cycle (Georgetown, Tex.) Tex.), 2015-01, Vol.14 (24), p.3864-3876
Main Authors: Angulo-Ibáñez, Maria, Rovira-Clavé, Xavier, Granados-Jaén, Alba, Downs, Bradley, Kim, Yeong C, Wang, San Ming, Reina, Manuel, Espel, Enric
Format: Article
Language:English
Subjects:
Animals
Apoptosis - drug effects
Apoptosis - genetics
Blotting, Western
Cell Cycle - drug effects
Cell Cycle - genetics
Cell Line, Tumor
Deoxyribonucleosides - metabolism
DNA Damage - drug effects
DNA Damage - genetics
Erythroid Cells - drug effects
Erythroid Cells - metabolism
Erythropoiesis - genetics
Erythropoiesis - physiology
HL-60 Cells
Humans
Jurkat Cells - drug effects
Jurkat Cells - metabolism
Mice
Mice, Knockout
Mitogen-Activated Protein Kinase 7 - genetics
Mitogen-Activated Protein Kinase 7 - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Thymidine - pharmacology
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Summary: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.
ISSN:1538-4101
1551-4005
DOI:10.1080/15384101.2015.1120914