RNA-DNA Differences Are Generated in Human Cells within Seconds after RNA Exits Polymerase II

•RNA sequences differ from DNA sequences beyond canonical RNA editing•RNA-DNA sequence differences (RDDs) are found in nascent RNAs•RDD formation occurs soon after transcript synthesis and before splicing

SummaryRNA sequences are expected to be identical to their corresponding DNA sequences. Here, we found all 12 types of RNA-DNA sequence differences (RDDs) in nascent RNA. Our results show that RDDs begin to occur in RNA chains ∼55 nt from the RNA polymerase II (Pol II) active site. These RDDs occur so soon after transcription that they are incompatible with known deaminase-mediated RNA-editing mechanisms. Moreover, the 55 nt delay in appearance indicates that they do not arise during RNA synthesis by Pol II or as a direct consequence of modified base incorporation. Preliminary data suggest that RDD and R-loop formations may be coupled. These findings identify sequence substitution as an early step in cotranscriptional RNA processing.

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