Chemical modification in RNA changes genetic code Novel transfer RNA modification establishes non-universal genetic code

A University of Tokyo research group discovered a novel modified base in one of the transfer RNA of echinoderm mitochondria, and has shown this modification plays a critical role in decoding a codon that deviates from the universal genetic code.

The so-called universal genetic code discovered in the 1960s was considered common to all living organisms and responsible for converting the genetic information contained in DNA to proteins, with all living things sharing the same code. This apparent conservation of the genetic code assumes that all domains of life evolved from a single interbreeding organism. However, genetic codes deviating from this universal code are frequently found in the genetic translation system in animal mitochondria, the organelles that serve as the powerhouse for generating energy in animal cells, raising an alternative theory that the genetic code is not fixed, but instead continues to evolve. Post-transcriptional modification of transfer RNA (tRNA) is thought to play a critical role in establishing such non-universal genetic codes. In the mitochondrial decoding system of echinoderms, including organisms like sea urchins and starfish, the AAA codon specifies the amino acid asparagine (Asn) instead of lysine (Lys). A previous study revealed that tRNA^Asn, the tRNA carrying asparagine, acquires pseudouridine (Ψ) at the second letter of the anticodon, and reads the AAA codon as asparagine. However, the mechanism by which tRNA^Lys, the tRNA carrying lysine, prevents misreading the AAA codon as lysine remained elusive.

The research group led by Assistant Professor Asuteka Nagao and Professor Tsutomu Suzuki of the Department of Chemistry and Biotechnology at the University of Tokyo's Graduate School of Engineering analyzed mitochondrial tRNA^Lys isolated from the Mesocentrotus nudus sea urchin, and discovered a novel modified base, hydroxyl-N⁶-threonylcarbamoyladenosine (ht⁶A), in a part adjacent to the anticodon. The researchers examined the codon recognition ability of this modification on the ribosome, the apparatus for protein synthesis in the cell, and found that it is capable of preventing tRNA^Lys from misreading the AAA codon as lysine. These results suggest that tRNA^Lys acquired a novel modification that contributes to the genetic code alteration of the AAA codon in echinoderm mitochondria.

This discovery not only adds new knowledge for RNA research, but also suggests that the establishment of a non-universal genetic code relies heavily on the chemical modification of tRNA.

"'There is a modified base with a molecular mass that we have never seen!' Such was our response to our exciting adventure of discovering the new modification with just the 16-dalton mass difference as our clue, and studying its molecular function," says Nagao. He continues, "That one oxygen atom governs the genetic code alteration was very interesting from both biochemical and evolutionary points of view. I would like to continue investigating a mechanism for building life that has not been discovered yet."