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A bacterial origin for the DNA of eukaryotes?

26 May. 2023
In an article published in the journal Nature Communication, scientists have made a surprising suggestion that gene transfer from bacteria to eukaryotes occurs. This discovery is based on the study of thymidylate synthase, an enzyme required for de novo DNA synthesis. These observations have provided new insight into the evolution of DNA by suggesting that the metabolic capacity of present-day eukaryotes to synthesise DNA may also have originated in bacteria and not only in archaea as previously thought.
A bacterial origin for the DNA of eukaryotes?
Part of the structure of the ThyX enzyme of the archaea 'Candidatus Prometheoarchaeum syntrophicum'.Credit: Filée, J., Becker, H.F., et al. (2023)

This text is a translation of the text published in French on the CNRS website. Scientists from the Optics and Biosciences Laboratory (LOB*) have taken part in this study.

Deoxyribonucleic acid, more commonly known as the DNA molecule, is the carrier of genetic information in all living organisms. The functional analysis and organisation of genomes, as well as the ways in which gene expression is regulated, still reveal the great complexity and diversity of genomes and their evolution.

DNA is structured as a double helix with alternating purine (adenine, guanine) and pyrimidine (cytosine, thymine) nitrogen bases. During replication, the process of DNA synthesis or duplication, thymidine biosynthesis is carried out by two distinct families of thymidylate synthases ThyA and ThX, depending on the species. More precisely, these two enzymes, essential for DNA synthesis catalyse the formation of deoxythymidine 5′-monophosphate (dTMP) by methylation of deoxyuridine 5′-monophosphate (dUMP). These two families of proteins therefore provide a unique enzymatic marker of the cell's ability to replicate its genetic information as they are directly involved in DNA synthesis.

In this study, the scientists investigated the evolution and function of thymidylate synthases (ThyX and ThyA) in the Asgard archaea. These prokaryotes appear to be closely related to eukaryotes, as some of their genes are similar to genes identified in eukaryotes. The phylogenies of the Asgard thymidylate synthase ThyX and other folate-dependent enzymes indicate their horizontal transmission from various bacterial groups. The scientists first validated the functionality of ThyX with genetic approaches by introducing the ThyX gene from the archaea 'Candidatus Prometheoarchaeum syntrophicum' (Psyn) into bacteria so that the bacteria express the ThyX Psyn protein. Analysis of the purified recombinant proteins showed that ThyX Psyn efficiently utilises bacterial-type folate and is inhibited by mycobacterial ThyX inhibitors. This result is surprising, as the majority of archaea tested experimentally are known to use molecules distinct from bacterial folates in methylation reactions.

Furthermore, phylogenetic analyses suggest that the eukaryotic thymidylate synthase, required for de novo DNA synthesis, is not closely related to archaeal enzymes and may have been transferred from bacteria to eukaryotes. Overall, our results suggest for the first time that the ability of eukaryotic cells to duplicate their genetic material involves both archaeal and bacterial replication proteins.

These unexpected results suggest the existence of a recent lateral gene transfer from bacteria to archaea, which would have considerably shaped the metabolism of Asgard archaea. In this study published in Nature Communications, the scientists shed new light on the early evolution of eukaryotic cells.

*LOB: a joint research unit CNRS, Inserm, École Polytechnique, Institut Polytechnique de Paris, 91120 Palaiseau, France