Department of Molecular Oncology, Göttingen Center for Molecular Biosciences, University of Göttingen, Göttingen, Germany.
Oncogene. 2010 May 13;29(19):2853-63. doi: 10.1038/onc.2010.42. Epub 2010 Mar 1.
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.
适当的细胞周期依赖性复制相关组蛋白的表达对于在复制过程中将 DNA 包装到染色质中是必不可少的。我们之前曾表明，细胞周期依赖性激酶-9（CDK9）控制组蛋白 H2B 单泛素化（H2Bub1），以指导特定的 mRNA 3'端加工蛋白招募到复制相关的组蛋白基因，并促进适当的前体 mRNA 3'端加工。我们现在表明，p53 通过诱导 G1 细胞周期阻滞来降低组蛋白特异性转录调节剂核蛋白，共济失调-毛细血管扩张症基因座（NPAT）的表达，从而影响 NPAT 基因的 E2F 依赖性转录。此外，NPAT 对于组蛋白 mRNA 3'端加工是必需的，并招募 CDK9 到复制相关的组蛋白基因。p53 激活或小干扰 RNA 敲低后 NPAT 表达的减少降低了 CDK9 的募集和复制相关的组蛋白基因转录，但增加了剩余组蛋白 mRNA 的多聚腺苷酸化。因此，我们提供了证据表明，G1 细胞周期阻滞的诱导（例如，p53 积累后）改变了组蛋白 mRNA 3'端加工，并揭示了在正常细胞过程中，前体 mRNA 3'端加工模式的调控开关的第一个机制，在肿瘤发生过程中可能会发生改变。
