RNA control of reverse transcription in a diversity-generating retroelement

Sumit Handa, Tapan Biswas, Jeet Chakraborty, Gourisankar Ghosh, Blair G. Paul and Partho Ghosh ()
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Sumit Handa: University of California San Diego
Tapan Biswas: University of California San Diego
Jeet Chakraborty: University of California San Diego
Gourisankar Ghosh: University of California San Diego
Blair G. Paul: Josephine Bay Paul Center
Partho Ghosh: University of California San Diego

Nature, 2025, vol. 638, issue 8052, 1122-1129

Abstract: Abstract Diversity-generating retroelements (DGRs) create massive protein sequence variation (up to 1030)1 in ecologically diverse microorganisms. A recent survey identified around 31,000 DGRs from more than 1,500 bacterial and archaeal genera, constituting more than 90 environment types2. DGRs are especially enriched in the human gut microbiome2,3 and nano-sized microorganisms that seem to comprise most microbial life and maintain DGRs despite reduced genomes4,5. DGRs are also implicated in the emergence of multicellularity6,7. Variation occurs during reverse transcription of a protein-encoding RNA template coupled to misincorporation at adenosines. In the prototypical Bordetella bacteriophage DGR, the template must be surrounded by upstream and downstream RNA segments for complementary DNA synthesis to be carried out by a complex of the DGR reverse transcriptase bRT and associated protein Avd. The function of the surrounding RNA was unknown. Here we show through cryogenic electron microscopy that this RNA envelops bRT and lies over the barrel-shaped Avd, forming an intimate ribonucleoprotein. An abundance of essential interactions in the ribonucleoprotein precisely position an RNA homoduplex in the bRT active site for initiation of reverse transcription. Our results explain how the surrounding RNA primes complementary DNA synthesis, promotes processivity, terminates polymerization and strictly limits mutagenesis to specific proteins through mechanisms that are probably conserved in DGRs belonging to distant taxa.

Date: 2025
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DOI: 10.1038/s41586-024-08405-w

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