Origin matters: spontaneous DNA-RNA hybrids do not form in trans as a source of genome instability

Multiple exogenous and endogenous genotoxic agents threaten the integrity of the genome, but one major source of spontaneous DNA damage is the formation of unscheduled DNA-RNA hybrids. These can be genetically detected by their ability to induce recombination. The origin of spontaneous hybrids has been mainly attributed to the nascent RNA formed co-transcriptionally in cis invading its own DNA template. However, it was unclear whether hybrids could also be spontaneously generated by RNA produced in a different locus (in trans). Using new genetic systems in the yeast Saccharomyces cerevisiae, we recently tested whether hybrids could be formed in trans and compromise genome integrity. Whereas we detected recombinogenic DNA-RNA hybrids in cis and in a Rad51-independent manner, we found no evidence for recombinogenic DNA-RNA hybrids to be formed with RNAs produced in trans. Here, we further discuss the implications in the field for the origin of genetic instability and the threats coming from RNAs.