CDK11 is required for transcription of replication-dependent histone genes

Replication-dependent histones (RDH) are required for packaging of newly synthetized DNA into nucleosomes during 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 N-terminal region binds FLASH, RDH-specific 3´end processing factor, which keeps the kinase on the chromatin. CDK11 phosphorylates serine 2 (Ser2) of the C-terminal domain (CTD) of RNA polymerase II (RNAPII), which is initiated at 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 due to the function of CDK11 in RDH gene expression. Thus, the reliance of RDH expression on CDK11 could explain why CDK11 is essential for growth of many cancers.