Section 72
Chapter 71,965

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

Pirngruber, J.; Johnsen, S.A.

Oncogene 29(19): 2853-2863


ISSN/ISBN: 0950-9232
PMID: 20190802
DOI: 10.1038/onc.2010.42
Accession: 071964634

Download citation:  

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.

PDF emailed within 0-6 h: $19.90