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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