The Super Elongation Complex (SEC) is a collection of proteins that plays a role in gene expression. Its primary function is to promote transcription, where genetic information from DNA is copied into RNA. It ensures genes are expressed accurately and at correct levels, which is fundamental for cellular activities.
Core Components of the Super Elongation Complex
The Super Elongation Complex is assembled from distinct protein subunits. Components include P-TEFb, a heterodimer of Cyclin T (typically Cyclin T1) and CDK9, a kinase enzyme. It also includes members of the ELL (Eleven-Nineteen Lysine-rich Leukemia) family, such as ELL1, ELL2, and ELL3. AFF (AF4/FMR2 family) proteins, specifically AFF1 and AFF4, often serve as scaffolding proteins. Other integral parts include ENL (Eleven-Nineteen Leukemia) and AF9 (ALL1-fused gene from chromosome 9). These diverse subunits facilitate transcription, though some variations, like SEC-L2 and SEC-L3, might lack certain ELL or EAF subunits.
Regulating Gene Transcription
The Super Elongation Complex controls gene transcription by overcoming transcriptional pausing. This occurs when RNA Polymerase II (Pol II), the enzyme synthesizing RNA, temporarily halts shortly after starting transcription, typically within 20 to 40 nucleotides from the gene’s promoter. Negative elongation factors, including DSIF (DRB sensitivity-inducing factor) and NELF (negative elongation factor), stabilize this paused state.
To release Pol II from this paused state and allow RNA synthesis, the SEC, through the kinase activity of its P-TEFb subunit, acts on specific targets. P-TEFb phosphorylates the C-terminal domain (CTD) of RNA Polymerase II, a flexible tail on the enzyme’s largest subunit. This modifies Pol II, signaling it to continue elongation.
P-TEFb also phosphorylates the Spt5 subunit of DSIF and the E subunit of NELF, both associated with the paused polymerase. This phosphorylation causes NELF to dissociate, while DSIF transitions from an inhibitory to a stimulatory factor. Coordinated phosphorylation by P-TEFb enables Pol II to resume movement along the DNA template, ensuring efficient RNA synthesis.
Role in Cellular Processes
The Super Elongation Complex is involved in fundamental cellular processes beyond transcription elongation. By ensuring efficient gene expression, SEC contributes to cell growth, allowing cells to increase in size and prepare for division. Its actions are also connected to cell differentiation, the process where cells become specialized. For instance, SEC influences the proliferation and differentiation of mouse embryonic stem cells and inner ear progenitor cells.
Proper SEC functioning is relevant for tissue and organ development. It regulates gene expression programs necessary for normal biological processes, including the induction of Hox genes, involved in body pattern formation during development. SEC’s role in gene expression is important for a cell’s ability to respond to stimuli and maintain cellular health.
Implications in Health and Disease
Dysregulation of the Super Elongation Complex has been connected to several disease states. In various cancers, particularly leukemias, SEC components are frequently involved in chromosomal translocations. For example, fusions between the MLL (mixed lineage leukemia) gene and SEC subunits like AFF1 or AFF4 can lead to aberrant activation of MLL target genes, promoting acute childhood leukemia. The MYC gene, a known oncogene, is a direct target of AFF4-containing SEC, and its dysregulation contributes to leukemia pathogenesis.
Beyond cancer, SEC is also implicated in viral infections. The human immunodeficiency virus (HIV) hijacks SEC to promote its gene expression, necessary for viral replication. The HIV Tat protein directly recruits P-TEFb, an SEC component, to the viral promoter, activating viral transcription. Understanding these interactions provides avenues for therapeutic interventions. For example, inhibiting CDK9, a P-TEFb component, with compounds like flavopiridol, can disrupt SEC function and has been explored in treating acute myeloid leukemia and chronic lymphocytic leukemia.