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¹ School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK
² Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, England, UK
³ School of Life Sciences, University of Dundee, Dundee DD1 4HN, Scotland, UK

Correspondence to B. Müller: b.mueller{at}abdn.ac.uk; or C. Smythe: carl.smythe{at}sheffield.ac.uk

DNA and histone synthesis are coupled and ongoing replication is required to maintain histone gene expression. Here, we expose S phase–arrested cells to the kinase inhibitors caffeine and LY294002. This uncouples DNA replication from histone messenger RNA (mRNA) abundance, altering the efficiency of replication stress–induced histone mRNA down-regulation. Interference with caffeine-sensitive checkpoint kinases ataxia telangiectasia and Rad3 related (ATR)/ataxia telangiectasia mutated (ATM) does not affect histone mRNA down- regulation, which indicates that ATR/ATM alone cannot account for such coupling. LY294002 potentiates caffeine's ability to uncouple histone mRNA stabilization from replication only in cells containing functional DNA-activated protein kinase (DNA-PK), which indicates that DNA-PK is the target of LY294002. DNA-PK is activated during replication stress and DNA-PK signaling is enhanced when ATR/ATM signaling is abrogated. Histone mRNA decay does not require Chk1/Chk2. Replication stress induces phosphorylation of UPF1 but not hairpin-binding protein/stem-loop binding protein at S/TQ sites, which are preferred substrate recognition motifs of phosphatidylinositol 3-kinase–like kinases, which indicates that histone mRNA stability may be directly controlled by ATR/ATM- and DNA-PK–mediated phosphorylation of UPF1.

Abbreviations used in this paper: APH, aphidicolin; AT, ataxia telangiectasia; ATM, AT mutated; ATR, AT and Rad3 related; CldU, chlorodeoxyuridine; DNA-PK, DNA-activated protein kinase; dU, deoxyuridine; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HBP, hairpin-binding protein; HU, hydroxyurea; IdU, iododeoxyuridine; kd, kinase dead; NHEJ, nonhomologous end joining; PIKK, phosphatidylinositol 3-kinase–like kinase; SLBP, stem-loop binding protein; wt, wild type.

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