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

Maria Angulo-Ibáñez, Xavier Rovira-Clavé, Alba Granados-Jaén, Bradley Downs, Yeong C. Kim, San Ming Wang, Manuel Reina, Enric Espel

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

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 Tcells.

Original languageEnglish (US)
Pages (from-to)3864-3876
Number of pages13
JournalCell Cycle
Volume14
Issue number24
DOIs
StatePublished - Jan 1 2015

Keywords

  • DNTP metabolism
  • Erythroid development
  • Erythropoiesis
  • Replication stress
  • Thymidine

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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    Angulo-Ibáñez, M., Rovira-Clavé, X., Granados-Jaén, A., Downs, B., Kim, Y. C., Wang, S. M., Reina, M., & Espel, E. (2015). Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis. Cell Cycle, 14(24), 3864-3876. https://doi.org/10.1080/15384101.2015.1120914