Induced G1 cell-cycle arrest controls replication-dependent histone mRNA 3′ end processing through p21, NPAT and CDK9

J. Pirngruber, S. A. Johnsen

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Proper cell cycle-dependent expression of replication-dependent histones is essential for packaging of DNA into chromatin during replication. We previously showed that cyclin-dependent kinase-9 (CDK9) controls histone H2B monoubiquitination (H2Bub1) to direct the recruitment of specific mRNA 3′ end processing proteins to replication-dependent histone genes and promote proper pre-mRNA 3′ end processing. We now show that p53 decreases the expression of the histone-specific transcriptional regulator Nuclear Protein, Ataxia-Telangiectasia Locus (NPAT) by inducing a G1 cell-cycle arrest, thereby affecting E2F-dependent transcription of the NPAT gene. Furthermore, NPAT is essential for histone mRNA 3′ end processing and recruits CDK9 to replication-dependent histone genes. Reduced NPAT expression following p53 activation or small interfering RNA knockdown decreases CDK9 recruitment and replication-dependent histone gene transcription but increases the polyadenylation of remaining histone mRNAs. Thus, we present evidence that the induction of a G1 cell-cycle arrest (for example, following p53 accumulation) alters histone mRNA 3′ end processing and uncover the first mechanism of a regulated switch in the mode of pre-mRNA 3′ end processing during a normal cellular process, which may be altered during tumorigenesis.

Original languageEnglish (US)
Pages (from-to)2853-2863
Number of pages11
JournalOncogene
Volume29
Issue number19
DOIs
StatePublished - May 13 2010

Keywords

  • CDK
  • Histone
  • MRNA processing
  • P53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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