Both prokaryotes and eukaryotes respond to the same RNA structure, initiating protein synthesis and thereby defying longstanding expectations. Prokaryotes and eukaryotes, it was long believed, relied on mutually exclusive translation-initiation signals.

The surprising result emerged when researchers based at the University of Colorado (UC) scrutinized a structured RNA molecule from a virus known to infect eukaryotic cells. Structured internal ribosome entry site (IRES) RNAs can manipulate ribosomes to initiate translation in eukaryotic cells, but an analogous RNA structure-based mechanism had never been observed in bacteria. Yet the IRES RNA studied by the UC scientists was able to initiate protein synthesis in bacteria.

“We wanted to explore whether it was possible to bypass mechanisms that were specific to each domain of life and find a signal capable of operating in both,” said Jeffrey Kieft, Ph.D., a professor of biochemistry and molecular genetics at CU and a Howard Hughes Medical Institute Early Career Scientist. “What we found bridges billions of years of evolutionary divergence.”

Dr. Keift and his colleagues published their results February 4 in Nature, in an article entitled, “Initiation of translation in bacteria by a structured eukaryotic IRES RNA.”

“We solved the crystal structure of this IRES bound to a bacterial ribosome to 3.8 Å resolution, revealing that despite differences between bacterial and eukaryotic ribosomes, this IRES binds directly to both and occupies the space normally used by transfer RNAs,” wrote the authors. “Initiation in both bacteria and eukaryotes depends on the structure of the IRES RNA, but in bacteria this RNA uses a different mechanism that includes a form of ribosome repositioning after initial recruitment.”

The article by Dr. Keift and colleagues was accompanied by a paper by Eric Jan, Ph.D., a professor of biochemistry and molecular biology at the University of British Columbia, who noted that by establishing the functionality of a eukaryotic ribosome-recruiting signal in prokaryotic bacteria, the UC scientists succeeded in “challenging the prevailing dogma that prokaryotic and eukaryotic ribosome recruitment are mutually exclusive.”

Dr. Jan’s paper, “Molecular biology: Signals across domains of life,” explained that the UC scientists’ reporter system seems to use a hybrid of eukaryotic and prokaryotic signals to promote protein synthesis in bacteria.

“In prokaryotic translation, RNA structures are dynamic, and some can control protein expression by either burying the [ribosome-binding site (RBS)] within their structure or altering conformation to expose the RBS for ribosome recruitment,” Dr. Jan wrote. “Although leaderless RNAs—which are translated in the absence of the signals that usually support ribosome binding and translation efficiency—can also function across domains, [the UC scientists] have shown for the first time that a bona fide signal in an RNA structure promotes protein synthesis in two domains of life.”

Cross-domain ribosome recruitment, Dr. Jan added, brings up a range of questions. Some of these questions concern mechanistic details, such as the means by which a bacterial ribosome may reposition itself from the IRES to the ribosome-binding site. Other questions mentioned by Dr. Jan are more general. For example, could the IRES be a remnant of a molecular fossil of the ancient RNA world that is widely presumed to have preceded the evolution of DNA and proteins?

According to Dr. Jan, the instance of cross-domain ribosome recruitment discovered by Dr. Kieft and colleagues “opens up the possibility that other RNA structures function as signals across domains, and that eukaryotes and bacteria have more in common than was previously thought.”








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