US scientists using novel chemical screening methods have discovered a new class of small molecules connected to RNA, suggesting that cellular RNA may be more chemically diverse than previously thought. 

The work could help scientists elucidate new biological roles for RNA, and may eventually lead to better understanding of the origin of life, say the researchers at Harvard University in Cambridge, Massachusetts.

Knowing the chemical structures of the molecules inside a cell - especially the structure of molecules as important as RNA - helps to shed light on aspects of biology, says chemical biologist David Liu, who led the research. ’Biological RNA has many important roles in the cell and some of those functions may depend on forms of RNA that have yet to be discovered or fully elucidated.’

For the past two decades, new functional roles for cellular RNA have been discovered at breathtaking pace compared to the less prolific growth of the known chemical forms of RNA. Previous approaches to understanding the chemical diversity of RNA and identifying small molecule-RNA conjugates have been limited in scope because they have been hypothesis driven, focusing on specific classes of RNA or small molecules. 

’We approached the problem from the other end of the spectrum, saying "let’s take all the RNA that the cell makes and develop a method for characterising its chemical diversity,"’ says Liu. Their ’discovery-orientated’ approach uses two broad chemical screening techniques that cast a much wider net and can process whole cellular RNA of any type, form or length and isolate small molecules connected to those RNAs.

’The methodology and chemistry they have used is fairly standard but they’ve used it in a novel and elegant way,’ says Jason Micklefield, Chair of Chemical Biology at the University of Manchester. Using their techniques, the team uncovered a previously unknown class of co-enzyme A (CoA)-linked RNAs. Currently, their biological function remains a mystery but the group are in the process of investigating their discovery. Liu speculates that the newly revealed small molecule groups linked to cellular RNAs might be involved in functions like controlling the expression of a gene that might be encoded by an RNA attached to a CoA, regulating the lifetime of RNA, or perhaps even participating in a form of templated synthesis.

Many models for how life began invoke an ’RNA World’ that must have been capable of basic forms of metabolism. Liu suggests that some of these hypothetical prebiotic functions of RNA that permitted metabolism may have taken advantage of small molecule-RNA conjugates beyond the examples that are already known.

However, ’there’s still quite a bit of work needed to unravel the exact structural nature of some of these small molecule-RNA conjugates before the full significance of this work is realised,’ says Micklefield. ’It’s difficult to say whether or not this is a remnant of an ancient RNA world. However, this work might indicate an alternative metabolic role for CoA.’

Liu’s team has found other examples of novel small molecule RNA conjugates from cells and are now developing a third method that is even more general, which doesn’t rely on chemical cleavage of the small molecule in order for it to be detected. ’Potentially this third method will enable us to cast an even wider net,’ adds Liu.

James Urquhart