title: Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis.
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 T cells.
authors.affiliation: a Department of Cell Biology ; Celltec-UB; Facultat de Biologia; Universitat de Barcelona ; Barcelona , Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Angulo-Ibáñez
authors.affiliation: a Department of Cell Biology ; Celltec-UB; Facultat de Biologia; Universitat de Barcelona ; Barcelona , Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Rovira-Clavé
authors.affiliation: a Department of Cell Biology ; Celltec-UB; Facultat de Biologia; Universitat de Barcelona ; Barcelona , Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Granados-Jaén
authors.affiliation: b University of Nebraska Medical Center; Nebraska Medical Center ; Omaha , NE USA.
authors.forename: Bradley
authors.initials: B
authors.lastname: Downs
authors.affiliation: b University of Nebraska Medical Center; Nebraska Medical Center ; Omaha , NE USA.
authors.forename: Yeong C
authors.initials: YC
authors.lastname: Kim
authors.affiliation: b University of Nebraska Medical Center; Nebraska Medical Center ; Omaha , NE USA.
authors.forename: San Ming
authors.initials: SM
authors.lastname: Wang
authors.affiliation: a Department of Cell Biology ; Celltec-UB; Facultat de Biologia; Universitat de Barcelona ; Barcelona , Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Reina
authors.affiliation: a Department of Cell Biology ; Celltec-UB; Facultat de Biologia; Universitat de Barcelona ; Barcelona , Spain.|c Department of Physiology and Immunology ; Facultat de Biologia; Universitat de Barcelona ; Barcelona ; Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Espel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D003853:Deoxyribonucleosides / Q000378:metabolism; D041905:Erythroid Cells / Q000187:drug effects / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics / Q000502:physiology*; D018922:HL-60 Cells; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013936:Thymidine / Q000494:pharmacology*
chemical_list: D003853:Deoxyribonucleosides; D048054:Mitogen-Activated Protein Kinase 7; D013936:Thymidine
keywords: dNTP metabolism; erythroid development; erythropoiesis; replication stress; thymidine