The study of the genome once seemed like a straightforward process: a specific short sequence of three nucleotide bases in DNA was a sign that indicated where a protein's sequence began. This three-base-pair sequence is known as a start site and is where an enzyme called RNA polymerase II starts to transcribe a DNA sequence into an RNA sequence. That RNA sequence is used to make the protein the gene encodes for.
But scientists have learned over the years that it’s not quite that simple. There are start sites scattered all over the genome, and sometimes they have no relation to a protein. It seems that cells are relatively promiscuous in their use of RNA polymerase II, and lots of non-functional products end up getting generated by this system. That means that the cell has to have robust quality check mechanisms to prevent these by-products of transcription from accumulating in the cell or causing damage.
Researchers have now learned more about the role of a protein complex called integrator in this process. Reporting in Molecular Cell, the study authors showed that integrator, which was previously shown to act to end transcription for a small group of small nuclear RNAs, actually works to terminate transcription early for many (if not all, they suggest) RNA polymerase II initiation events. In the case of such early termination, a very short transcript is generated that can easily and quickly be disposed of by the cell.
Many protein-coding genes that produce long transcripts have features that are able to prevent early termination. So, integrator is able to reduce the production of aberrant or wasteful transcripts while thousands of start sites are still able to retain their place in the genome. This enables the cell to select for the best transcripts; a reservoir of transcribed sequences is generated, some of which can be turned into functional genes while others can be discarded.
In the case of snRNAs, integrator can terminate a transcript early, but the cell may retain the transcript to produce a functional RNA molecule.
When mutations occur that cause the inactivation of parts of the integrator complex, neurodevelopmental disease can occur. If portions of integrator are expressed at abnormally high levels, there is an increase in a process that is linked to tumor metastasis called epithelial to mesenchymal transition. Integrator’s activity, therefore, seems to be critical, and subject to careful control.
This work may eventually open up our understanding of these neurodevelopmental disorders and may lead to new ways to treat them.