Gene expression relies on a fundamental process: transcription, by which the genetic information contained in DNA is copied into RNA. This mechanism, driven by RNA polymerase II for messenger RNAs in eukaryotes, must be rigorously controlled not only to start at the correct location, but also to end precisely. Improper termination can lead to the production of aberrant transcripts, which can interfere with other genes and affect the overall organization of the genome. This final step, called transcription termination, is therefore just as critical as initiation or elongation, although it has long remained less studied.
In a recent study conducted at the Institut Cochin (Université Paris Cité, Inserm, CNRS), researchers identified a central player in this process: the SPT6 protein. Known for its role in accompanying the polymerase during elongation, SPT6 is also essential for properly completing transcription. The absence of SPT6 leads to an uncontrolled pursuit of RNA polymerase II activity beyond the natural boundaries of genes, generating abnormal transcripts that can invade neighboring regions of the genome. This "transcriptional leak" underlines the importance of a rigorously controlled termination.

SPT6, PCF11 and PNUTS: a network of partners for a controlled termination

SPT6 does not work alone. The researchers highlighted its cooperation with two other key factors: PCF11, a component of the cleavage and polyadenylation complex, and PNUTS, a regulator of the speed of the RNA polymerase II at gene ends. PCF11 promotes the detachment of RNA polymerase II from the DNA strand by recognizing specific signals at the end of genes, while PNUTS works by slowing down the polymerase to promote efficient termination.
The study demonstrates that SPT6 plays a central role in orchestrating the combined action of these two partners. By facilitating their recruitment to RNA polymerase II, SPT6 helps ensure that transcription is completed in a clean and accurate manner. In the event of a failure of this monitoring network, transcription is abnormally prolonged, favoring the emergence of aberrant transcripts, especially in sensitive regions such as promoters where unwanted RNAs (PROMPTs) can appear.
This control of termination is crucial not only to avoid collision between neighboring transcripts, but also to maintain a faithful and orderly reading of the genetic program as a whole.

Ending transcription to better protect the genome 

This study sheds light on fundamental mechanisms in the regulation of gene expression that have long been underestimated. It highlights that transcription termination is an active, complex process that mobilizes several factors in synergy. By preventing the production of abnormal transcripts, SPT6, in collaboration with PCF11 and PNUTS, directly contributes to preserving the organization and stability of the genome.
A cell's ability to activate the right genes at the right time, but also to properly interrupt their transcription, is essential for maintaining its identity, function, and balance. These results remind us that the end of a process is as decisive as its beginning, and open up new perspectives for better understanding the fine regulation of gene expression in human cells.

Publication

Bejjani F, Ségéral E, Mosca K, Lecourieux A, Bakail M, Hamoudi M, Emiliani S. Overlapping and distinct functions of SPT6, PNUTS, and PCF11 in regulating transcription termination. Nucleic Acids Res. 2025 Feb 27;53(5):gkaf179. doi: 10.1093/nar/gkaf179. PMID: 40103229; PMCID: PMC11915507.