All mammalian genes can be set on pause

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Washington, Apr 30 (ANI): All mammalian genes apparently have a layer of control that acts just like the pause button on your DVR, according to new evidence in embryonic stem cells.

The researchers have said that the results show that the pausing phenomenon, previously thought to be a peculiarity of particular genes, is actually a much more general feature of the genome.

"We're coming to the realization that we've been missing out on an entire second step in the control of gene expression. There's tremendous excitement and some healthy debate too," said Richard Young of the Whitehead Institute and Massachusetts Institute of Technology.

The researchers have shown that the infamous cancer gene known as c-Myc plays a major role in the pause release of many genes throughout the genome.

Thus, their fundamentally important findings may ultimately have practical application in the treatment of some of the nastiest cancers, said the researchers.

For decades, scientists have known that transcription is controlled by the recruitment of DNA binding factors to promoters, where they act as a kind of molecular Velcro for the polymerase enzymes that copy DNA into the mRNA templates for proteins,

But now, the researchers have shown that other players cause the recruited polymerases to freeze in their places - in effect pausing gene activity.

It is the job of still other transcription factors to act as a pause release.

As evidence for the importance of the pausing function, a genome-wide analysis of embryonic stem cells showed that the bulk of polymerases can be found adjacent to promoters at any given time, even when the genes in question are some of the most actively transcribed.

Pause factors (known as DSIF and NELF) are usually there too, consistent with the notion that they bind the enzyme after it has only just gotten started transcribing the DNA.

The interactions of still other players, including one that is recruited by the transcription factor c-Myc, must then release the pausing for the genes to come back 'on'.

Young said he initially thought the pausing process might be fairly unique to embryonic stem cells, but he doesn't think so any more.

At the beginning of the study, they also expected the embryonic cells would show this sort of pausing at select developmental genes only. However, they found that polymerase was paused at about 75 percent of all promoters.

"We found it was occurring everywhere - at all genes. The polymerases come for a visit and then they pile up downstream of the promoter," said Young.

They make only a very small stretch of RNA before they stop, awaiting the signal to continue.

Some of the paused polymerases appear to remain in their suspended state indefinitely, he said.

Young said he thinks this second layer of control likely offers cells some added flexibility.

He also claimed that the connection of this pausing process to c-Myc could make some waves.

Thus, the new findings offer new insight into how Myc works and a new rationale and strategy for trying to shut it down as a way to treat cancer.

The findings are reported in the latest issue of the journal Cell, a Cell Press publication. (ANI)

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