Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress

Austin, Wayne R.; Armijo, Amanda L.; Campbell, Dean O.; Singh, Arun S.; Hsieh, Terry; Nathanson, David; Herschman, Harvey R.; Phelps, Michael E.; Witte, Owen N.; Czernin, Johannes; Radu, Caius G.

doi:10.1084/jem.20121061

Cited by 77 publications

(103 citation statements)

References 49 publications

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“…Deoxynucleoside salvaging during B cell, T cell and erythroid development is necessary to fine tune dNTP levels and avoid replication stress in their highly proliferative progenitors. 18,19 The results presented here show that erythroid progenitors without Erk5 have higher dTTP levels, associated with enhanced mutagenesis and inefficient erythropoiesis in bone marrow, but not in the spleen. On average, bone marrow contains twice the amount of thymidine than spleen.…”

Section: Discussionmentioning

confidence: 72%

“…On average, bone marrow contains twice the amount of thymidine than spleen. 19 Thymidine salvaging in bone marrow could generate replication stress in highly proliferative haematopoietic precursors of Erk5 ¡/¡ VavCre mice if dNTP metabolism is not properly geared, and these are subsequently forced to immigrate to more permissive niches such as the spleen. 18 In addition to erythroid progenitors, B cell development also showed signs of stress, as the mature B220 high B cell population was underrepresented in Erk5 ¡/¡ VavCre marrow.…”

Section: Discussionmentioning

confidence: 99%

“…It is therefore conceivable that the elevated thymidine concentration naturally occurring in haematopoietic tissues 19 could produce conditions for replication stress if Erk5 is absent. To test this notion, we bred loxP-flanked Erk5 mice (Erk5 fl/fl mice) with Vav-Cre-transgenic mice to generate an animal model with excision of Erk5 in the haematopoietic lineage (here called Erk5 -/-VavCre) (Fig.…”

Section: Mice With Erk5-deficient Haematopoietic Cells Show Ineffectimentioning

confidence: 99%

“…Fuelled by extracellular deoxynucleosides imported into the cell, 17 the salvage pathway is necessary for proper haematopoietic development. 18,19 Haematopoietic tissues contain high thymidine levels, which increases the cellular dTTP levels produced by the salvage pathway. 19 A high dTTP concentration prevents UTP incorporation into DNA and replication stress in erythroid and lymphoid lineages.…”

Section: Introductionmentioning

confidence: 99%

“…19 A high dTTP concentration prevents UTP incorporation into DNA and replication stress in erythroid and lymphoid lineages. 18,19 Alterations in the activity of enzymes metabolising nucleotides can lead to mutagenesis and tumourigenesis in vitro and in vivo [20][21][22] and produce developmental defects in lymphoid and erythroid lineages, 18,23 underscoring the importance of nucleotide metabolism for proper haematopoietic development.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2015

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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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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Mice With Erk5-deficient Haematopoietic Cells Show Ineffectimentioning

confidence: 99%