The production of RNA from a DNA template is performed by RNA polymerases (RNAPs) through the process of transcription. Due to their complexities, eukaryotic genomes rely on specialized RNAPs to produce their different classes of RNA. Notably, mammalian cells harbor three RNAPs (RNAPI, II and III), which individually differ in their regulation, especially at the level of how they terminate transcription. An international collaboration between laboratories in Denmark, the United Kingdom and Japan now detail a termination mechanism of RNAPII, sharing unexpected homology with how RNAPIII and even prokaryotic RNAPs terminate their activities.

Over the past decade, it has been established that the so-called Integrator (INT) complex acts to terminate RNAPII during the early stages of transcription. Moreover, at snRNA genes, which produce a class of short functional RNAPII transcripts, INT was described to perform a crucial RNA maturation step. This step was widely considered to be required for transcription termination of RNAPII at these genes, but central aspects of this notion were at odds with known features of INT transcription termination activity.

INT activity in snRNA maturation is uncoupled from RNAPII transcription termination

Postdoctoral researchers Lee Davidson and Jérôme Rouvière set out to investigate this discrepancy. Gratifyingly, they uncovered that the role of INT in snRNA maturation is completely uncoupled from RNAPII transcription termination. Instead, termination depends on a simple stretch of Ts (T-tracts) in the DNA template, akin to the mechanism utilized by eukaryotic RNAPIII and prokaryotic RNAPs.

Remarkably, such transcription termination at T-tracts is not only restricted to snRNA genes. In fact, genome-wide analysis revealed it to be generally abundant both in the early stages of the RNAPII transcription cycle as well as at its end. These areas are both regions of the DNA where RNAPII transcribes notably slower. This therefore suggests that T-stretches play a critical role in terminating unwanted transcription events.

This research derived from a collaboration between the teams of Steven West, The Living Systems Institute, University of Exeter, Torben Heick Jensen, Department of Molecular Biology and Genetics, Aarhus University, Nicholas J. Proudfoot, Sir William Dunn School of Pathology, Oxford and Takayuki Nojima, Medical Institute of Bioregulation, Kyushu University. The study is now online at the journal Genes Development.

The research paper

DNA-directed termination of mammalian RNA polymerase II. Lee Davidson, Jérôme O Rouvière, Rui Sousa-Luís, Takayuki Nojima, Nicholas Proudfoot, Torben Heick Jensen and Steven West. Genes and Development, Published in Advance November 4, 2024, doi:10.1101/gad.351978.124.

SUPPLEMENTARY INFORMATION

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Study type:

Research article

External funding:

This work is funded by the Wellcome Trust for supporting this work with an Investigator Award 223106/Z/21/Z to S.W. Research in N.J.P.’s laboratory was also funded by a Wellcome Trust Investigator Award (107928/Z/15/Z). Research in T.H.J.’s laboratory was supported by the Danish Cancer Society, the Lundbeck Foundation, and the Novo Nordisk Foundation (NNF) (ExoAdapt grant 31199). The project used the University of Exeter Sequencing Service funded by a Wellcome Trust multiuser equipment grant (218247/Z/19/Z). 

Conflict of interest:

None

For further information, please contact

Professor Torben Heick Jensen - thj@mbg.au.dk
Department of Molecular Biology and Genetics, Aarhus University, Denmark