The multi-tasking P-TEFb complex

Abstract

P-TEFb (CycT1:Cdk9), the metazoan RNA polymerase II Ser2 C-terminal domain (CTD) kinase, regulates transcription elongation at many genes and integrates mRNA synthesis with histone modification, pre-mRNA processing, and mRNA export. Recruitment of P-TEFb to target genes requires deubiquitination of H2Bub, phosphorylation of H3S10, and the bromodomain protein, Brd4. Brd4 activates growth-related genes in the G1 phase of the cell cycle and can also tether P-TEFb to mitotic chromosomes, possibly to mark sites of active transcription throughout cell division. P-TEFb co-operates with c-Myc during transactivation and cell transformation, and also requires SKIP (c-Ski-interacting protein), an mRNA elongation and splicing factor. Some functions of the P-TEFb/Ser2P CTD are executed by the Spt6 transcription elongation factor, which binds directly to the phosphorylated CTD and recruits the Iws1 ('interacts with Spt6') protein. Iws1, in turn, interacts with the REF1/Aly nuclear export adaptor and stimulates the kinetics of mRNA export. Given the prominent role of Spt6 in regulating chromatin structure, the CTD-bound Spt6:Iws1 complex may also control histone modifications during elongation. Following transcription, P-TEFb accompanies the mature mRNA to the cytoplasm to promote translation elongation.

Figure 1

Transcription factors implicated in P-TEFb recruitment and function. Activators may recruit P-TEFb directly (e.g. Tat, c-Myc), or indirectly through binding to Brd4. P-TEFb recruitment is also linked to H3S10P, which can be mediated by MSK1,2 or Pim1, which can be recruited through c-Myc:TRRAP complexes. TRRAP is a frequent target of DNA activators and associates with HAT complexes that acetylate chromatin and stabilize binding of Brd4. P-TEFb functionally cooperates with proteins like SKIP to activate transcription and RNAPII CTD phosphorylation links elongation with downstream events required for gene expression.

Figure 2

Spt6 is recruited to RNAPII at an early step in transcription and is required for elongation at some, but not all, genes. Phosphorylation of the RNAPII CTD by P-TEFb induces binding of Spt6 and its partner, Iws1, which binds to the REF1/Aly mRNA export adaptor and stimulates the kinetics of nuclear mRNA export, potentially through transfer of REF1/Aly to the cap binding complex on the nascent mRNA.