The C-terminal domain (CTD) of RNA polymerase II (Pol II) consists of conserved heptapeptide repeats that function as a binding platform for different protein complexes involved in transcription, RNA processing, export, and chromatin remodeling. The CTD repeats are subject to sequential waves of posttranslational modifications during specific stages of the transcription cycle. These patterned modifications have led to the postulation of the “CTD code” hypothesis, where stage-specific patterns define a spatiotemporal code that is recognized by the appropriate interacting partners. Here, we highlight the role of CTD modifications in directing transcription initiation, elongation, and termination. We examine the major readers, writers, and erasers of the CTD code and examine the relevance of describing patterns of posttranslational modifications as a “code.” Finally, we discuss major questions regarding the function of the newly discovered CTD modifications and the fundamental insights into transcription regulation that will necessarily emerge upon addressing those challenges. 1. Introduction The transcription of DNA to RNA in eukaryotes is catalyzed by three structurally related RNA polymerases, with each acting on a different class of genes [1]. RNA polymerase I synthesizes most of the ribosomal RNA (rRNA) subunits while RNA polymerase III synthesizes tRNAs, 5S rRNA, and other small RNAs [2–4]. These two polymerases account for 75% and 15% of transcription in the cell, respectively [5]. However, the most studied polymerase is RNA Polymerase II (Pol II), which is responsible for the transcription of protein-coding genes, small nuclear RNA (snRNA), and small nucleolar RNA (snoRNA) [6–8]. In higher eukaryotes, Pol II generates long noncoding RNA (lncRNA) and microRNA (miRNA) [9, 10]. Pol II also transcribes cryptic unstable transcripts (CUTs) and stable unannotated transcripts (SUTs), which are degraded after synthesis [11–13]. The suppression of CUTs is important to prevent inappropriate transcription within ORFs, to enhance processivity during transcription elongation, and to prevent gene silencing via histone deacetylation [14–18]. Of the twelve Pol II subunits, five are common between the three polymerases [1, 19–21]. It is believed that the specific functions attributed to each polymerase arise from the combined action of remaining nonidentical subunits and other factors that associate with them. An especially unique feature of Pol II is the carboxy-terminal domain (CTD) of its large subunit Rpb1 (Figure 1(a)). The CTD serves as the primary point of
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