Antiviral reverse transcriptases reveal the evolutionary origin of telomerase

Abstract Defense-associated reverse transcriptases (DRTs) employ diverse and distinctive mechanisms of cDNA synthesis to protect bacteria against viral infection. However, much of DRT family diversity remains unstudied. Here we identify a new antiviral defense system, DRT10, that associates with a non-coding RNA (ncRNA) to catalyze processive, protein-primed synthesis of tandem-repeat DNA. Repeat addition is dictated by sequence and structural features of the ncRNA that have direct parallels in the RNA component of telomerase. Remarkably, a phylogenetic analysis of RTs across domains of life reveals an unexpected link between DRT10 and telomerase that is further supported by structural comparisons and mechanistic evidence. These findings expand the repertoire of reverse transcription mechanisms in antiviral defense and point to a bacterial origin for telomerase. One-Sentence Summary Insights from antiviral defense systems reveal an unexpected bacterial origin for the mechanism of chromosome maintenance by eukaryotic telomerase. Competing Interest Statement Columbia University has filed a patent application related to this work. S.H.S. is a co-founder and scientific advisor to Dahlia Biosciences, a scientific advisor to CrisprBits andPrime Medicine, and an equity holder in Dahlia Biosciences and CrisprBits. The remaining authors declare no competing interests.