TY - JOUR
T1 - Erk5 contributes to maintaining the balance of cellular nucleotide levels and erythropoiesis
AU - Angulo-Ibáñez, Maria
AU - Rovira-Clavé, Xavier
AU - Granados-Jaén, Alba
AU - Downs, Bradley
AU - Kim, Yeong C.
AU - Wang, San Ming
AU - Reina, Manuel
AU - Espel, Enric
N1 - Publisher Copyright:
© 2015 Taylor & Francis Group, LLC.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
KW - DNTP metabolism
KW - Erythroid development
KW - Erythropoiesis
KW - Replication stress
KW - Thymidine
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U2 - 10.1080/15384101.2015.1120914
DO - 10.1080/15384101.2015.1120914
M3 - Article
C2 - 26697837
AN - SCOPUS:84964066304
SN - 1538-4101
VL - 14
SP - 3864
EP - 3876
JO - Cell Cycle
JF - Cell Cycle
IS - 24
ER -