Summary: Researchers report inosine could be a potential route to the first RNA and the origin to life on Earth.
Our prehistoric Earth, bombarded with asteroids and lightening, rife with bubbling geothermal pools, may not seem hospitable today. But somewhere in the chemical chaos of our early planet, life did form. How? For decades, scientists have attempted to create miniature replicas of infant Earth in the lab. There, they hunt for the primordial ingredients that created the essential building blocks for life.
It’s attractive to chase our origin story. But this pursuit can bring more than just thrill. Knowledge of how Earth built its first cells could inform our search for extraterrestrial life. If we identify the ingredients and environment required to spark spontaneous life, we could search for similar conditions on planets across our universe.
Today, much of the origin-of-life research focuses on one specific building block: RNA. While some scientists believe that life formed from simpler molecules and only later evolved RNA, others look for evidence to prove (or disprove) that RNA formed first. A complex but versatile molecule, RNA stores and transmits genetic information and helps synthesize proteins, making it a capable candidate for the backbone of the first cells.
To verify this “RNA World Hypothesis,” researchers face two challenges. First, they need to identify which ingredients reacted to create RNA’s four nucleotides–adenine, guanine, cytosine, and uracil (A, G, C, and U). And, second, they need to determine how RNA stored and copied genetic information in order to replicate itself.
So far, scientists have made significant progress finding precursors to C and U. But A and G remain elusive. Now, in a paper published in PNAS, Jack W. Szostak, Professor of Chemistry and Chemical Biology at Harvard University, along with first-author and graduate student Seohyun (Chris) Kim suggest that RNA could have started with a different set of nucleotide bases. In place of guanine, RNA could have relied on a surrogate–inosine.
“Our study suggests that the earliest forms of life (with A, U, C, and I) may have arisen from a different set of nucleobases than those found in modern life (A, U, C, and G),” said Kim. How did he and his team arrive at this conclusion? Lab attempts to craft A and G, purine-based nucleotides, produced too many undesired side products. Recently, however, researchers discovered a way to make versions of adenosine and inosine–8-oxo-adenosine and 8-oxo-inosine–from materials available on primeval Earth. So, Kim and his colleagues set out to investigate whether RNA constructed with these analogs could replicate efficiently.
But, the substitutes failed to perform. Like a cake baked with honey instead of sugar, the final product may look and taste similar, but it doesn’t function as well. The honey-cake burns and drowns in liquid. The 8-oxo-purine RNA still performs, but it loses both the speed and accuracy needed to copy itself. If it replicates too slowly, it falls apart before completing the process. If it makes too many errors, it cannot serve as a faithful tool for propagation and evolution.
Despite their inadequate performance, the 8-oxo-purines brought an unexpected surprise. As part of the test, the team compared 8-oxo-inosine’s abilities against a control, inosine. Unlike its 8-oxo counterpart, inosine enabled RNA to replicate with high speed and few errors. It “turns out to exhibit reasonable rates and fidelities in RNA copying reactions,” the team concluded. “We propose that inosine could have served as a surrogate for guanosine in the early emergence of life.”
Szostak and Kim’s discovery could help substantiate the RNA world hypothesis. In time, their work might confirm RNA’s primary role in our origin story. Or, scientists might find that early Earth offered multiple paths for life to grow. Eventually, armed with this knowledge, scientists could identify other planets that have the essential ingredients and determine whether we share this universe or are, indeed, alone.
Source: Caitlin McDermott-Murphy – Harvard
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is adapted from the Harvard news release.
Original Research: Open access research for “Inosine, but none of the 8-oxo-purines, is a plausible component of a primordial version of RNA” by Seohyun Chris Kim, Derek K. O’Flaherty, Lijun Zhou, Victor S. Lelyveld, and Jack W. Szostak in PNAS. Published December 3 2018.
Inosine, but none of the 8-oxo-purines, is a plausible component of a primordial version of RNA
The emergence of primordial RNA-based life would have required the abiotic synthesis of nucleotides, and their participation in nonenzymatic RNA replication. Although considerable progress has been made toward potentially prebiotic syntheses of the pyrimidine nucleotides (C and U) and their 2-thio variants, efficient routes to the canonical purine nucleotides (A and G) remain elusive. Reported syntheses are low yielding and generate a large number of undesired side products. Recently, a potentially prebiotic pathway to 8-oxo-adenosine and 8-oxo-inosine has been demonstrated, raising the question of the suitability of the 8-oxo-purines as substrates for prebiotic RNA replication. Here we show that the 8-oxo-purine nucleotides are poor substrates for nonenzymatic RNA primer extension, both as activated monomers and when present in the template strand; their presence at the end of a primer also strongly reduces the rate and fidelity of primer extension. To provide a proper comparison with 8-oxo-inosine, we also examined primer extension reactions with inosine, and found that inosine exhibits surprisingly rapid and accurate nonenzymatic RNA copying. We propose that inosine, which can be derived from adenosine by deamination, could have acted as a surrogate for G in the earliest stages of the emergence of life.