Core canonical histones are required in the S phase of the cell cycle to pack newly synthetized DNA, therefore the expression of their genes is highly activated during DNA replication. In mammalian cells, this increment is achieved by both enhanced transcription and 3′ end processing. In this paper, we described positive cofactor 4 (PC4) as a protein that contributes to the regulation of replication-dependent histone gene expression. We showed that PC4 influences RNA polymerase II recruitment to histone gene loci in a cell cycle-dependent manner. The most important effect was observed in S phase where PC4 knockdown leads to the elevated level of RNA polymerase II on histone genes, which corresponds to the increased total level of those gene transcripts. The opposite effect was caused by PC4 overexpression. Moreover, we found that PC4 has a negative effect on the unique 3′ end processing of histone pre-mRNAs that can be based on the interaction of PC4 with U7 snRNP and CstF64. Interestingly, this effect does not depend on the cell cycle. We conclude that PC4 might repress RNA polymerase II recruitment and transcription of replication-dependent histone genes in order to maintain the very delicate balance between histone gene expression and DNA synthesis. It guards the cell from excess of histones in S phase. Moreover, PC4 might promote the interaction of cleavage and polyadenylation complex with histone pre-mRNAs, that might impede with the recruitment of histone cleavage complex. This in turn decreases the 3′ end processing efficiency of histone gene transcripts.

中文翻译：

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阳性辅因子4（PC4）有助于调节复制依赖的规范组蛋白基因表达。

细胞周期的S期需要核心规范组蛋白来包装新合成的DNA，因此在DNA复制过程中其基因的表达被高度激活。在哺乳动物细胞中，这种增加是通过增强转录和3'末端加工实现的。在本文中，我们将阳性辅助因子4（PC4）描述为一种有助于调节复制依赖性组蛋白基因表达的蛋白。我们表明，PC4以细胞周期依赖性方式影响RNA聚合酶II募集到组蛋白基因位点。在S期观察到最重要的影响，其中PC4敲低导致组蛋白基因上RNA聚合酶II的水平升高，这与这些基因转录本的总水平升高相对应。相反的作用是由PC4过表达引起的。而且，我们发现PC4对组蛋白前mRNA的独特3'末端加工有负面影响，这可以基于PC4与U7 snRNP和CstF64的相互作用。有趣的是，这种效应并不取决于细胞周期。我们得出结论，PC4可能会抑制RNA聚合酶II的募集和复制依赖性组蛋白基因的转录，以维持组蛋白基因表达与DNA合成之间非常微妙的平衡。它可以保护细胞免受S期过量的组蛋白的侵害。此外，PC4可能促进裂解和聚腺苷酸化复合物与组蛋白前体mRNA的相互作用，这可能会阻碍组蛋白裂解复合物的募集。这继而降低了组蛋白基因转录物的3'末端加工效率。