Induced G1 cell-cycle arrest controls replication-dependent histone mRNA 3' end processing through p21, NPAT and CDK9.
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.
Pirngruber
J
J
Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University of Göttingen, Göttingen, Germany.
Johnsen
S A
SA
D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000172:deficiency / Q000235:genetics; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D050704:E2F4 Transcription Factor / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D006657:Histones / Q000235:genetics*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D026723:Polyadenylation / Q000187:drug effects; D026721:RNA 3' End Processing / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050704:E2F4 Transcription Factor; D006657:Histones; C101693:NPAT protein, human; D009687:Nuclear Proteins; C501972:PAF1 protein, human; D012333:RNA, Messenger; D050717:Retinoblastoma-Like Protein p130; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D042863:Cyclin-Dependent Kinase 9; D006918:Hydroxyurea