Vestigial no more

Deploying doppelgängers to distract pesky hangers-on isn’t a tactic reserved for paparazzi-plagued Hollywood heartthrobs. Some genes use look-alikes as decoys to distract mobs of interfering molecules, a new study shows.

The decoys, known as pseudogenes, are defective copies of protein-encoding genes. Many pseudogenes can make RNA copies of the instructions contained within their DNA, but have flaws that prevent the next step in the process, making proteins.

Because pseudogenes don’t make proteins, most biologists have thought of the doppelgängers as vestigial copies of functioning genes But a new study, published in the June 24 Nature, shows that pseudogenes aren’t dead yet, and may in fact be important regulators of their protein-producing twins.

This discovery that pseudogenes may indeed have a function could transform biology, says Pier Paolo Pandolfi, a cancer geneticist and biologist at Beth Israel Deaconess Medical Center in Boston and Harvard Medical School who led the study. The finding has already altered the perspectives of people in his lab, he says. “Now we are unable to think the same. It changes the way we do biology on a daily basis.”

In particular, Pandolfi’s group found that RNA from a pseudogene called PTENP1 acts as a decoy by drawing tiny regulatory molecules called microRNAs away from the pseudogene’s protein-producing counterpart, a powerful anticancer gene called PTEN.

MicroRNAs are small pieces of RNA that bind messenger RNAs, also known as mRNAs — the intermediates between genes and their proteins. MicroRNA binding either causes the mRNA to be degraded or blocks protein production, effectively quashing activity of the gene. Many kinds of microRNAs can bind to the PTEN mRNA and reduce its ability to make protein. That could be disastrous, because cells are very sensitive to levels of PTEN protein. Lowering levels of the protein just 20 percent from normal is enough to cause precancerous changes in mice, the researchers previously discovered.

That’s where PTENP1 comes in. The pseudogene looks just like PTEN, except for a mutation that prevents it from making protein. Pandolfi reasoned that the microRNAs attracted to PTEN wouldn’t be able to tell the twin genes apart and that some microRNAs might go after the pseudogene, thereby protecting PTEN from too much attention.

When researchers tested that idea by making more PTENP1 mRNA in cells, levels of PTEN protein increased, indicating that the pseudogene was acting as a sponge to mop up microRNAs that would otherwise reduce PTEN production. Removing PTENP1 from cells had the opposite effect — with nothing to distract the microRNAs, the regulatory molecules latched on to PTEN and squelched protein production.

The researchers also found that tumors from colon cancer patients were sometimes missing PTENP1, indicating that the pseudogene could help protect against tumors. A cancer-causing gene called KRAS also has a pseudogene, KRAS1P, that may be involved in stimulating tumor growth.

It is too early to tell whether the thousands of pseudogenes in the human genome all help regulate their protein-coding siblings, or if the cancer genes are special cases, says Frank Furnari, a cancer biologist at the University of California, San Diego. But the finding gives biologists an unexpected type of gene regulation to explore. “For sure we know the importance of microRNAs, and now to have this mechanism by which microRNAs are regulated by what we thought was junk DNA is somewhat surprising and exciting.”