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Into regulation of transcription termination

Regulation of gene expression is essential for efficient protein production with faulty mechanisms being linked to cancer. EU researchers have made substantial inroads into unravelling the molecular basis behind transcription termination at genetic and epigenetic levels.
Into regulation of transcription termination
The gene transcription cycle involves initiation, elongation and termination. Successful termination releases the RNA polymerase (Pol II) for recycling and depends downstream on RNA polyadenylation with poly(A) and terminator sequences.

Transcription termination is critical for normal cell function as this process helps prevent transcriptional interference. Alterations in this process have been linked with changes in length to three prime untranslated region (3'-UTR) messenger RNA leading to diseases such as cancer. Despite this, research into mammalian mechanisms of translation control has been scant.

The TRXTERMSIGN (Genetic and epigenetic signature of transcription termination) project aimed to address this research gap on a genome-wide basis using computational, genetic and biochemical technologies.

A complex system, various mechanisms were investigated including cotranscriptional cleavage (CoTC)-type terminator elements and nuclear function of the human DICER protein. Published in Nature, the team described a novel mechanism involving R-loops that leads to a cascade and the reinforcement of Pol II pausing prior to efficient termination of transcription.

Looking specifically at the tumour suppressor protein breast cancer type 1 (BRCA1), the researchers found that this molecule is recruited to RNA Pol II pause sites, where it is required for a DNA damage repair mechanism. Results were published in the peer-reviewed Molecular Cell journal.

Additionally, TRXTERMSIGN scientists produced genome-wide data on chromatin binding of a cleavage and polyadenylation factor in the mammalian system. They also created a chromatin map for the cleavage and polyadenylation factor subunit (PCF11), an important protein in transcription termination and investigated the effects of its knock-out. The resulting model of PCF11 action shows that preferential chromatin binding occurs in areas that demand efficient termination, especially when gene density is high and susceptible to transcriptional interference.

Significantly, the team have mapped several post-translational modifications that could affect the function of important transcription factors. Using PCF11, they identified a site that regulates binding to RNA Pol II, enabling termination.

TRXTERMSIGN research results have application potential in all areas of medicine as changes in RNA 3' processing affect systems at all levels. Study findings should help researchers devise innovative treatments for related diseases, including cancer and viral infections.

Related information

Keywords

Regulation, transcription termination, genetic, epigenetic, TRXTERMSIGN
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