MYC and Transcription Elongation

Abstract

Most transcription factors specify the subset of genes that will be actively transcribed in the cell by stimulating transcription initiation at these genes, but MYC has a fundamentally different role. MYC binds E-box sites in the promoters of active genes and stimulates recruitment of the elongation factor P-TEFb and thus transcription elongation. Consequently, rather than specifying the set of genes that will be transcribed in any particular cell, MYC's predominant role is to increase the production of transcripts from active genes. This increase in the transcriptional output of the cell's existing gene expression program, called transcriptional amplification, has a profound effect on proliferation and other behaviors of a broad range of cells. Transcriptional amplification may reduce rate-limiting constraints for tumor cell proliferation and explain MYC's broad oncogenic activity among diverse tissues. TRANSCRIPTIONAL REGULATIONT ranscription factors bind specific DNA sequences and regulate the recruitment and activity of the transcription apparatus at genes (Ptashne and Gann 1997; Lee and Young 2013). The process of transcription consists of at least three steps: initiation, elongation, and termination (Fuda et al. 2009;Malik and Roeder 2010;Zhou et al. 2012). During initiation, the transcription apparatus, which consists of RNA polymerase II (Pol II) and various cofactors, is recruited to genes by transcription factors. A short transcript is produced by Pol II and pause factors typically induce pausing 20 -50 bp downstream of the transcriptional start site. Elongation proceeds after the elongation factor P-TEFb, which consists of Cdk9 and cyclin T, is recruited, and phosphorylates the pause factors and Pol II. Transcription termination is stimulated by recognition of polyadenylation site sequences by factors associated with Pol II during elongation.It has long been clear that specific transcription factors are responsible for recruiting Pol II to selected genes during transcription initiation, but evidence emerged in the last decade that argues for an additional level of control at the pause-release and/or elongation stage of transcription for a large number of genes (Fuda et al. 2009;Nechaev and Adelman 2011;Zhou et al. 2012;Conaway and Conaway 2013). For example, in various human cells, Pol II was found to occupy the promoters of the majority ( 70%) of protein-coding genes, but full-length transcripts were detected at only a subset of these genes (Guenther et al. 2007). Similarly, a large fraction of Drosophila genes with roles in devel-

Role of MYC in Medulloblastoma

“…This functional redundancy implies that MYC and MYCN may have similar roles. These homologs contain conserved MYC boxes, and similar basic helix-loop-helix (bHLH)-zipper structures that recognize the same DNA motif when dimerized with MAX (see Eisenman 2013; Rahl and Young 2013 MYCN into the MYC locus rescues murine development, strongly suggesting major functional redundancy (Malynn et al 2000). However, MYC and MYCN also possess long stretches of nonrelated amino acid sequences, which raises the possibility that they are functionally diverse.…”

Oncogenic Mechanisms in Burkitt Lymphoma

“…Thus, the translocation of MYC in BL uncouples MYC expression in the GC from the natural process of positive selection in the LZ. Recent evidence suggests that one function of MYC is to amplify the expression of all genes that are active in a cell (Lin et al 2012;Nie et al 2012;Levens 2013;Rahl and Young 2014), and thus the role of MYC in BL may be to augment the centroblast phenotype. In this context, it is noteworthy that TCF-3, which encodes the transcription factor E2A, is characteristically and selectively expressed in centroblasts and is central to BL biology (see below).…”

Concepts to Target MYC in Pancreatic Cancer

“…Among others, such complexes include epigenetic writers, like histoneacetyltransferases (HAT), epigenetic readers, like BET proteins, or the basal transcription machinery, like the TATA box-binding protein (TBP; refs. [70][71][72]). An important role for MYC in the release of the paused RNA Pol II at the proximal promoter of MYC-bound genes was demonstrated (73).…”

“…Therefore, inhibition of processes bridging MYC to RNA Pol II can be used to inhibit MYC-dependent programs. MYC can interact and recruit the pTEFb factors cyclin T1 and CDK9 (72). CDK9 phosphorylates Ser2 of the C-terminal domain of RNA Pol II, needed for productive transcriptional elongation.…”