DNA-activated protein kinase functions in a newly observed S phase checkpoint that links histone mRNA abundance with DNA replication

Berndt Marino Muller, Jane Blackburn, Carmen Feijoo, Xiujie Zhao, Carl Smythe

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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 heparin-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.

Original languageEnglish
Pages (from-to)1385-1398
Number of pages14
JournalJournal of Cell Biology
Volume179
Issue number7
DOIs
Publication statusPublished - 24 Dec 2007

Keywords

  • cell-cycle regulation
  • gene-expression
  • damage checkpoint
  • binding-protein
  • mammalian-cells
  • ATR
  • stability
  • arrest
  • CHK1
  • degradation

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