Transcription does not end simply because RNA polymerase II (Pol II) reaches the apparent end of a gene. A new review by Song, Hu and Chen presents termination as an active, highly regulated stage of gene expression—one that determines where transcription stops, what happens to the resulting RNA and how the surrounding genome is maintained. The analysis brings together findings from metazoans and yeast to explain how cells terminate transcription across both protein-coding genes and the vast noncoding regions of the genome.

Pol II termination is essential for defining transcriptional boundaries. If polymerase continues beyond the appropriate endpoint, it can interfere with neighboring genes, generate abnormal RNA molecules and disturb chromatin organization. Conversely, premature termination can prevent the production of functional transcripts. The review emphasizes that cells use multiple termination pathways rather than a single universal mechanism, with the choice depending on genomic location, RNA processing signals and the fate assigned to the emerging transcript.

At the 3′ ends of most protein-coding genes, termination is closely linked to cleavage and polyadenylation. As Pol II transcribes the gene’s 3′-end signals, protein complexes recognize sequence elements in the nascent RNA and promote cleavage. The upstream RNA is then typically stabilized by the addition of a poly(A) tail, while the downstream RNA remains associated with the polymerase and can be degraded. This processing step helps destabilize the transcription complex and supports the release of Pol II from DNA, making termination inseparable from the maturation of messenger RNA.

This canonical pathway also illustrates why transcription termination is not a single moment but a coordinated sequence of molecular events. RNA cleavage, polyadenylation, polymerase slowing, factor recruitment and degradation of downstream RNA all contribute to dismantling the elongation complex. The review describes these processes as part of a broader network in which RNA processing and termination communicate continuously. The outcome is not only a defined gene boundary but also an RNA molecule prepared for export, translation or nuclear surveillance.

A distinct pathway operates near promoters, where Pol II frequently initiates short-lived transcription that does not proceed into a complete gene. The Integrator–PP2A complex, known as INTAC, has emerged as a major regulator of this promoter-proximal termination. By cleaving nascent transcripts and helping disengage Pol II, INTAC can restrict short transcriptional bursts and shape the production of noncoding RNAs. This mechanism is particularly important for controlling transcription from regulatory elements and for preventing low-level initiation from developing into unwanted genomic traffic.

The review also highlights Pol II turnover as another route to termination. The E3 ubiquitin ligase complex CRL3ARMC5 can target Pol II for regulated destruction, providing a way to remove polymerase molecules that become stalled or persist at inappropriate genomic locations. This pathway differs from conventional termination because it relies on the controlled elimination of the transcription machinery itself. By clearing problematic polymerases, cells may prevent stalled complexes from obstructing replication, transcription or repair.

RNA surveillance provides an additional layer of control through the relationship between the 5′ cap and transcriptional competence. Newly synthesized RNA is normally capped, and this cap can influence whether a transcript remains associated with productive gene expression pathways or is directed toward nuclear decay. Cap-dependent surveillance can therefore help distinguish properly initiated and processed transcripts from aberrant RNAs generated by pervasive or premature transcription. In this way, termination and RNA quality control cooperate to decide which transcription products are allowed to persist.

A central theme of the review is the role of termination in suppressing pervasive transcription. The genome contains many promoters, enhancers and other regions capable of initiating transcription, but most of these events must be limited in length and carefully contained. Termination pathways prevent transcripts from spreading into neighboring regulatory domains or genes. When these safeguards fail, readthrough transcription can alter gene regulation and create abnormal RNA species, placing additional pressure on RNA processing and nuclear degradation systems.

The consequences extend to genome stability. Inefficient termination can increase the formation of R-loops, structures in which a newly synthesized RNA hybridizes with its DNA template and displaces the second DNA strand. Although R-loops can have physiological roles, excessive or persistent structures expose single-stranded DNA and can obstruct replication and repair. The resulting conflicts between transcription and replication may contribute to DNA damage and rearrangements. By terminating transcription efficiently, cells reduce the opportunity for these harmful structures to accumulate.

The review ultimately presents termination as a decision-making hub connecting transcription, RNA processing, export, degradation and chromatin regulation. Canonical cleavage and polyadenylation, INTAC-mediated promoter-proximal termination, CRL3ARMC5-dependent Pol II turnover and cap-dependent surveillance represent complementary strategies for controlling where transcription ends and what happens afterward. Understanding how these pathways cooperate may clarify why termination defects are associated with disrupted gene expression and genome instability, while also revealing how cells keep the coding and noncoding portions of the genome under precise molecular control.

Subject of Research: Transcription termination by RNA polymerase II across protein-coding and noncoding genomic loci

Article Title: Mechanisms of transcription termination across the coding and noncoding loci of the genome

Article References: Song, A., Hu, M. & Chen, F.X. “Mechanisms of transcription termination across the coding and noncoding loci of the genome.” Nature Reviews Molecular Cell Biology (2026). https://doi.org/10.1038/s41580-026-01005-8

Image Credits: AI Generated

DOI: 10.1038/s41580-026-01005-8

Keywords: RNA polymerase II, transcription termination, cleavage and polyadenylation, Integrator, INTAC, CRL3ARMC5, RNA surveillance, pervasive transcription, R-loops, genome stability

Tags: chromatin maintenance during transcriptiongene transcription termination mechanismsgenome organization and stabilitymetazoan and yeast transcriptionnoncoding genome transcriptionregulation of gene expressionRNA cleavage and polyadenylationRNA polymerase II regulationRNA processing signalstranscription termination pathwaystranscriptional boundary definitiontranscriptional read-through prevention