Much as in M. C. Escher's famous lithograph, novel RNA enzymes can assemble mirror image versions of themselves.

Much as in M. C. Escher's famous lithograph, novel RNA enzymes can assemble mirror image versions of themselves.

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Mirror image RNA enzymes may hold clues to origin of life

Like a pair of hands that appear as mirror images of one another, biomolecules, such as DNA and RNA, come in left-handed and right-handed forms. Normally, enzymes that recognize one mirror image form won’t touch the other. But researchers have isolated RNA enzymes, known as ribozymes, that synthesize RNAs of the opposite handedness. As esoteric as this may sound, similar mirror image–making RNAs may have played a role in the early evolution of life.

Researchers consider RNA a likely central figure in the origin of life. That’s because, like DNA, the molecule can store genetic information, and like proteins it can act as a chemical catalyst that speeds up normally slow reactions. Many researchers believe that life likely got its start in an “RNA world” where RNAs evolved to replicate other RNA molecules. In this scenario, the more specialized DNA and proteins arose later.

Like DNA, RNA is made up of four nucleotide bases, in this case the nucleotides abbreviated A, U, C, and G. When ribozymes copy RNA, they start with a single strand of RNA that they use as a template to form a strand containing the complementary bases. C is complementary to G, and A is complementary to U. So if a template strand with the letters ACCGU were placed in a test tube with individual nucleotides floating around, the complementary bases U, G, G, C, and A would grab onto their partners on the template strand. Then for these complementary bases to form an intact complementary RNA strand, the ribozyme would need to chemically weld the adjacent nucleotides together, much as boxcars next to one another must be linked together to form a train.

The difference between RNA nucleotides and boxcars, however, is that individual nucleotides can come in either right- or left-handed forms, known as D- and L-nucleotides, respectively. All naturally occurring RNAs today are D-RNAs, but researchers can create L-RNAs in the lab. Normally, a ribozyme containing D-nucleotides won’t touch L-nucleotides, and ribozymes containing L-nucleotides won’t touch D-nucleotides. But if an opposite-handed nucleotide in a would-be complementary strand twists just right, it can fool a ribozyme and get integrated into the growing strand—with drastic consequences. Thirty years ago, researchers including Gerald Joyce, then a graduate student at the Salk Institute for Biological Studies in San Diego, California, showed that if a nucleotide with the opposite handedness was incorporated into a growing D- or L-RNA complementary strand, it shut down all further growth. “It acted like poison,” says Joyce, who is now at the Scripps Research Institute in San Diego.

This discovery raised a conundrum for origin-of-life researchers that they’ve struggled with ever since. Before life got its start, D- and L-nucleotides would likely have been equally abundant in the primordial soup. If so, how would RNA enzymes ever have managed to get the RNA copying process going without it being poisoned?

Now, Joyce and his postdoc Jonathan Sczepanski have found a possible solution. Online this week in Nature, they show that by using a technique called test-tube evolution they were able to generate ribozymes capable of assembling RNA strands of the opposite handedness in the presence of a mixture of D- and L-RNA nucleotides. What’s more, when they started with a D-RNA ribozyme, they found that it preferred to work on an L-RNA template to synthesize an L-RNA complementary strand. Likewise, they prepared L-RNA ribozymes that synthesized D-RNA complementary strands from D-RNA templates. And both the D- and L-RNA ribozymes were able to make mirror image copies of themselves.

The ribozymes work this trick in an unconventional way, Joyce explains. Instead of recognizing where complementary RNA bases (say an A and a U) reach across the template and complementary strand to recognize one another, the enzymes recognize the overall shape of the assembling RNA bases on the complementary strand and link whatever pieces wind up next to each other.

“It’s a very exciting advance towards RNA-catalyzed RNA replication,” says Jack Szostak, an origin-of-life researcher at Harvard University who was not involved with the work. However, Szostak says, it still begs the question of where such D-RNA and L-RNA ribozymes would have come from in the first place.

The answer may be forever lost to history, Joyce says. But the new work does suggest that if these cross-copying ribozymes arose early on, they could have copied both mirror versions of RNA to propel the evolution of more complex RNAs. If one of those later, more complex RNAs—say a D-RNA—proved more capable, it could have encouraged the copying of its own kind, and promoted the single-handedness in nucleotides that we see today.

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