RNA polymerase II carboxy-terminal domain kinases: Emerging clues to their function

The cloning of the largest subunit of RNA polymerase II (pol II) from mouse and Saccharomyces cerevisiae in 1985 (3, 28) revealed a remarkable and highly conserved domain known as the pol II carboxy-terminal domain (CTD). This domain has intrigued researchers interested in the mechanisms regulating gene expression ever since its discovery, because of both its simplicity and its complexity. The CTD is simple in the sense that it consists entirely of repeats of the 7-amino-acid consensus sequence YSPTSPS. The mouse (28) and human (125) CTDs consist of 52 repeats, of which 21 exactly match the consensus while 20 differ at only a single position (Table 1). This same consensus sequence is conserved in other eukaryotes, with 27 repeats in budding yeast (18 exact and 5 with a single difference) (3) and 45 repeats in the more divergent Drosophila CTD (2 exact and 15 with a single difference) (4, 133). In contrast to its simple repetitive composition, the functions of the CTD are quite complex, being involved in all major steps of mRNA formation, including transcription initiation and elongation, capping, splicing, and 3' end processing (30, 42). With such critical roles in gene expression, it is not surprising that the CTD is essential for viability (4, 8, 86, 133) and has been the subject of intense study. The CTD is not simply a passive component of the transcription and RNA processing machinery but also performs important regulatory roles. This regulatory aspect of the CTD was first suggested by the finding that the CTD is phosphorylated (13) and, more importantly, that phosphorylation of the CTD varies during the transcription cycle (54, 73). These insights stimulated searches for the CTD-specific kinase, but instead of a single kinase, several kinases that are capable of phosphorylating the CTD in vitro have been discovered. The goal of this review is to describe the present understanding of these candidate CTD kinases and their functions. The reader is referred to excellent comprehensive reviews for more detailed discussion regarding the role of the CTD during transcription (30) and as an organizing scaffold during mRNA synthesis (42); these topics will only be summarized here briefly as necessary.