Mechanism of Strand-Biased and Codon-Contexted Somatic Hypermutation in Immunity and Cancer: Implications of the Finding that Adar-Deaminases Can Directly Mediate a-to-I Editing on Both the DNA and Rna Moieties of Rna:dna Hybrids.

Authors: Edward J Steele, Robyn A Lindley

This paper simply links the recent findings of Zheng, Lorenzo and Beal on ADAR-mediated DNA and RNA deamination at RNA:DNA hybrids, to our previous work on strand-biased and codon-context mutation signatures in B lymphocytes (Ig SHM) and codon-contexted exome-wide point mutation patterns in cancer genomes. We conclude that in vivo the A-to-I DNA editing component at RNA: DNA hybrids occurring in Transcription Bubbles, while important, is of far lower A-to-I editing efficiency than in dsRNA substrates (as shown in Zheng et al). Indeed the RNA moiety of RNA:DNA hybrids is also edited at similar lower frequency (relative to dsRNA substrates). Further if the A-to-I DNA editing at RNA:DNA hybrids were the sole cause of A-to-I (read as A-to-G) mutation events in vivo then the exact opposite strand biases at A:T base pairs (T>>>A) of what is actually observed (A>>>T) would be predicted. Thus we conclude that the extreme strand-biased somatic mutation patterns documented by us in vivo should be logically interpreted by the predicted sequential steps of the RNA/RT-based mechanism.

Comments: 10 Pages.

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[v1] 2017-02-24 16:25:29

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