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

Abstract

Endogenous thymidine plays a critical role in the induction of replication stress in thymocytes.

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

“…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.…”

“…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.…”

“…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.…”

“…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.…”

“…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.…”