Anshabo et al.
CDK9 in Cancer
initial step of expression and revolves around the interaction of mammalian genes, ready to resume transcription elongation
multiple host factors with the CTD of RNAP II. The CTD (35). While the exact purpose of RNAP II pausing is not
consists of tandem heptapeptide repeats (52 in mammals) of clarified, some of the proposed functions include (1):
the consensus sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser increasing the accessibility of genes that would otherwise have
(Y1S2P3T4S5P6S7) (32, 33). These host factors guide RNAP II a high chance of being condensed into nucleosomes (2), allowing
to gain access to transcription sites, initiate and elongate rapid and synchronous gene activation (3), integrating multiple
transcription, and couple transcription of messenger RNA regulatory signals, and (4) a checkpoint for coupling elongation
(mRNA) with its processing, including capping, splicing, and with 5’ end-capping of nascent RNA (36). Two factors, namely
polyadenylation (32–34). DRB sensitivity-inducing factor (DSIF) and negative elongation
Formerly, transcriptional initiation was viewed as the main factor (NELF), cooperate in pausing RNAP II (37, 38).
checkpoint for regulating transcription, while little emphasis was The RNAP II requires the kinase activity of P-TEFb to
given to transcriptional elongation. This viewpoint, however, has overcome the pause and continue elongation (Figure 5) (14).
changed considerably as it now becomes apparent that Upon recruitment to the paused site by bromodomain-
elongation is a highly dynamic and strictly regulated stage of containing protein 4 (BRD4), P-TEFb phosphorylates one of
transcription (32). Shortly after RNAP II initiates transcription the four subunits of NELF (NELF-E or RD) and the human SPT5
and synthesizes 20-50 nucleotides of the nascent RNA, it is (hSPT5) subunit of DSIF (39, 40). These phosphorylation steps
engaged by factors which significantly hinder its ability to liberate NELF from RNAP II, while converting DSIF into a
continue elongation (9, 33). In fact, the majority of RNAP II is positive elongation factor to track along elongating RNAP II (39,
found paused at the promoter-proximal regions of most 41). Simultaneously, P-TEFb also phosphorylates the CTD of
FIGURE 5 | Control of transcriptional elongation by P-TEFb. During active transcription, BRD4 recruits JMJD6 to 7SK snRNP anchored to anti-pause enhancers on
chromatin. JMJD6 demethylates both H4R3me and the 5’ hairpin of 7SK RNA, breaking chromatin binding of the former and exposing the latter for degradation
(Labelled as 1). Concurrently, acetylated histone (H3KAC)-bound BRD4 interacts with and extracts P-TEFb from 7SK snRNP (2). Protein phosphatases (PP2B and
PP1a) also assist in the release of P-TEFb from 7SK snRNP by dephosphorylating CDK9 pThr186 (3). After release, CDK9 is re-phosphorylated on Thr186 by CDK7
and delivered by BRD4-JMJD6 to RNAP II that has been paused in the proximal promoter region. At this site, P-TEFb phosphorylates DSIF, NELF, and RNAP II CTD
(4), allowing productive elongation (5).
Frontiers in Oncology | www.frontiersin.org 6 May 2021 | Volume 11 | Article 678559
