Replication-dependent histones (RDH) are required for packaging of newly synthetized DNA into nucleosomes during the S phase when their expression is highly upregulated. However, the mechanisms of this upregulation in metazoan cells remain poorly understood. Using iCLIP and ChIP-seq, we found that human cyclin-dependent kinase 11 (CDK11) associates with RNA and chromatin of RDH genes primarily in the S phase. Moreover, its amino-terminal region binds FLASH, an RDH-specific 3'-end processing factor, which keeps the kinase on the chromatin. CDK11 phosphorylates serine 2 (Ser2) of the carboxy-terminal domain of RNA polymerase II (RNAPII), which is initiated when RNAPII reaches the middle of RDH genes and is required for further RNAPII elongation and 3'-end processing. CDK11 depletion leads to decreased number of cells in S phase, likely owing to the function of CDK11 in RDH gene expression. Thus, the reliance of RDH expression on CDK11 could explain why CDK11 is essential for the growth of many cancers.

中文翻译：

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CDK11 是复制依赖性组蛋白基因转录所必需的。

在 S 期，当新合成的 DNA 表达高度上调时，需要复制依赖性组蛋白 (RDH) 将其包装到核小体中。然而，后生动物细胞中这种上调的机制仍然知之甚少。使用 iCLIP 和 ChIP-seq，我们发现人类细胞周期蛋白依赖性激酶 11 (CDK11) 主要在 S 期与 RDH 基因的 RNA 和染色质相关。此外，它的氨基末端区域与 FLASH（一种 RDH 特异性 3' 末端加工因子）结合，使激酶保持在染色质上。CDK11 磷酸化 RNA 聚合酶 II (RNAPII) 的羧基末端结构域的丝氨酸 2 (Ser2)，当 RNAPII 到达 RDH 基因的中间时启动，并且是进一步 RNAPII 延伸和 3' 端加工所必需的。CDK11 耗竭导致 S 期细胞数量减少，可能是由于 CDK11 在 RDH 基因表达中的功能。因此，RDH 表达对 CDK11 的依赖可以解释为什么 CDK11 对许多癌症的生长至关重要。