26 November 2021
Finding fresh RNA enzymes in the human genome
Published online 24 March 2021
Genomic screen uncovers a novel ribozyme in humans.
A genomic screen has revealed a new ribozyme in the human genome that belongs to a previously unidentified class of these RNA enzymes. The discovery broadens our understanding of the diversity of ribozymes and demonstrates that expanded screening could uncover new ones.
Ribozymes are a special class of RNA that can catalyse reactions, such as cleaving themselves in two. In addition to their biological importance, ribozymes could have biotechnological applications, making it important to understand their biology and diversity. Ribozymes are common in bacteria and certain eukaryotes but have not been found abundantly in mammals. To date, only four have been found in the human genome.
Researchers at China’s Huaqiao University, together with Kourosh Salehi-Ashtiani of the UAE’s New York University Abu Dhabi, designed an intricate screen to uncover a genome’s ribozymes. They generated a library of short DNA fragments from the human genome and transcribed them into RNA. The RNA fragments were placed in conditions conducive to ribozyme cleavage, which leaves characteristic chemical end groups on each of the cleaved RNA pieces. They then created conditions for an enzyme to digest uncleaved RNA and one part of each cleaved RNA, leaving only the second cleavage product intact.
The screen produced a list of 28 candidate ribozymes in the genome. One was a known human ribozyme, validating the screen’s effectiveness. Of the remainder, only a single candidate showed cleavage activity in follow-up tests.
The team analysed this ribozyme’s biochemical properties and secondary structure and concluded it belongs to a new class of ribozymes, expanding our picture of ribozyme diversity. This is the first ribozyme to be found embedded within a ubiquitous class of long non-coding RNA, raising the possibility that this class may have as-yet uncharacterized functions based on ribozyme activity.
The researchers also traced the ribozyme’s evolutionary history. It first appeared in mammals between 65 and 130 million years ago but only became able to cleave itself in the common ancestors of humans, chimpanzees and gorillas—though the gorilla version has lost its cleavage ability. “One of our most exciting findings is the realization that a totally novel ribozyme could evolve very recently in the hominin lineage,” says Philipp Kapranov, senior author of the study. “Our discovery suggests that catalytic RNAs can and do evolve in modern organisms, and this opens up a possibility that other types of RNA enzymes also exist in humans and other complex organisms.”
Marcos de la Peña, an RNA specialist at Spain’s Institute for Plant Molecular and Cellular Biology, who was not involved in this study, calls this an impressive piece of work. His group, among others, showed years ago that ribozymes are found in most genomes, but the prevailing view has been that ribozymes are an ancient genetic element “which can be domesticated for newer functions in ‘more evolved’ organisms such as humans,” he says. “Everything in this work indicates that the motif appeared de novo.”
Further work will be needed to uncover this ribozyme’s function and understand why it was lost in gorillas but retained in humans, chimpanzees and bonobos. Kapranov and his colleagues also plan to expand the screen to look for other types of ribozymes in humans and other organisms.
Chen, Y., Qi, F., et al. Hovlinc is a recently evolved class of ribozyme found in human lncRNA. Nat. Chem. Biol. http://dx.doi.org/10.1038/s41589-021-00763-0 (2021).