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Gene silencing by a triple helix

Posted on 08/04/2019 | in 杭州龙凤 | by

The dihydrofolate reductase (DHFR) gene is typically viewed as what's called a housekeeping gene. It provides basic and essential functions to dividing cells (it helps produce the bases used in DNA and RNA), and would be considered uninteresting if it weren't the target for some forms of chemotherapy. Despite being a bit mundane, however, a paper that will appear in Nature suggests that the regulation of the gene is anything but dull. Two promoters, interfering RNAs, and a DNA-DNA-RNA triple helix all play a role in keeping this gene expressed only when cells need it. HangZhou Night Net

Like many genes, DHFR has more than one promoter (diagrammed above)—the site at which proteins bind to kick off the process of making an RNA message (mRNA) out of the gene. When cells are dividing, the gene is active and 99 percent of the mRNAs start at the second promoter, which we'll call Pn for normal. When cells stop dividing, most of the mRNA starts at the first promoter, which we'll call Pi for reasons that will become clear later. The researchers were surprised to find, however, that these messages didn't actually contain the full sequence needed to make functional DHFR protein—instead, the stopped shortly after Pn.

The researchers speculated that the Pi activity might inhibit (hence the i) the function of Pn. Did this effect require the two promoters to be linked on the same strand of DNA? The researchers answered this by putting both promoters on separate pieces of DNA. Even when separated, expression of the a normal RNA from the Pi blocked mRNA expression from Pn. They also showed that the inhibitory activity of the RNA made from Pi required sequences from the Pn area. If a sequence was inserted between Pi and Pn that stopped the Pi messages before they reached Pn, the inhibitory effect vanished.

All of which raises the question of what the Pi RNA is doing. The researchers got a hint that it was physically acting at the Pn. They discovered that the presence of the Pi RNA interfered with the binding of Pn by proteins needed for mRNA production. In other words, when the Pi RNA was present, the proteins weren't, and Pn was inactive. Scanning the area around Pn revealed a few stretches of sequence that can undergo an unusual form of base pairing. With DNA still base paired normally, the RNA bases can pair with the exterior of the those on the DNA, forming a triple helix. They confirmed that this actually takes place by running an assay that physically separated the double-stranded DNA from the DNA-RNA complex.

The paper is significant in part because it comes at a time where we're increasingly recognizing the important role that non-coding RNAs play in regulating gene expression. Past results have shown a number of examples where RNAs have either targeted mRNAs for degradation or blocked their use in protein production. The new paper suggests yet another way that non-coding RNAs can regulate gene expression. Because researchers have some sense of the sequences that can form a triple helix, it's possible that genome-wide analysis of promoters can identify other candidates for this sort of regulation.

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