GSE212194
ATR kinase supports normal proliferation in the early S phase by preventing replication resource exhaustion [RNA-seq]
The ATR kinase, which coordinates cellular responses to DNA replication stress, is also   essential for the proliferation of normal unstressed cells. Although its role in the replication stress   response is well defined, the mechanisms by which ATR supports normal cell proliferation remain   elusive. Here, we show that Atr is dispensable for the viability of G0-arrested naïve B cells. However,   upon cytokine-induced proliferation, Atr-deficient B cells initiate DNA replication efficiently in early S   phase, but by mid-S phase they display dNTP depletion, fork stalling, and replication failure.   Nonetheless, productive DNA replication can be restored in Atr-deficient cells by pathways that  suppress origin firing, such as downregulation of CDC7 and CDK1 kinase activities. Together, these   findings indicate that ATR supports the proliferation of normal unstressed cells by tempering the pace   of origin firing during the early S phase to avoid exhaustion of dNTPs and other replication factors. Overall design: We studied gene expression profiles in murine primary B cells ATR-proficient (CD21-Cre Atr+/C) or ATR-deficient (CD21-Cre AtrC/-) at different time points and cell cycle stages, namely G0 (0 h), G1 (10 h) and S (24 h) phase. Furthermore, we also analyzed the gene expression profile upon 14 hour treatment with CDC7 and CDK1 inhibitors.