Nonenzymatic assembly of active chimeric ribozymes from aminoacylated RNA oligonucleotides

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 7
• Main Authors: Radakovic, Aleksandar, DasGupta, Saurja, Wright, Tom H, Aitken, Harry R M, Szostak, Jack W
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15.02.2022
• Subjects: Amino acid sequence; Amino acids; Aminoacylation; Assembly; Base Sequence; Biological Sciences; Catalysis; DNA; Nucleic Acid Conformation; Nucleotide sequence; Oligonucleotides; Polymers; Protein biosynthesis; Protein synthesis; Proteins; Ribozymes; RNA ligase; RNA, Catalytic - metabolism; RNA, Transfer - genetics; RNA, Transfer - metabolism; Substrates; Transfer RNA Aminoacylation - physiology; translation; ribosome; ribozymes; aminoacylation; RNA
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2116840119

Aminoacylated transfer RNAs, which harbor a covalent linkage between amino acids and RNA, are a universally conserved feature of life. Because they are essential substrates for ribosomal translation, aminoacylated oligonucleotides must have been present in the RNA world prior to the evolution of the ribosome. One possibility we are exploring is that the aminoacyl ester linkage served another function before being recruited for ribosomal protein synthesis. The nonenzymatic assembly of ribozymes from short RNA oligomers under realistic conditions remains a key challenge in demonstrating a plausible pathway from prebiotic chemistry to the RNA world. Here, we show that aminoacylated RNAs can undergo template-directed assembly into chimeric amino acid-RNA polymers that are active ribozymes. We demonstrate that such chimeric polymers can retain the enzymatic function of their all-RNA counterparts by generating chimeric hammerhead, RNA ligase, and aminoacyl transferase ribozymes. Amino acids with diverse side chains form linkages that are well tolerated within the RNA backbone and, in the case of an aminoacyl transferase, even in its catalytic center, potentially bringing novel functionalities to ribozyme catalysis. Our work suggests that aminoacylation chemistry may have played a role in primordial ribozyme assembly. Increasing the efficiency of this process provides an evolutionary rationale for the emergence of sequence and amino acid-specific aminoacyl-RNA synthetase ribozymes, which could then have generated the substrates for ribosomal protein synthesis.