ADAR deaminase A-to-I editing of DNA and RNA moieties of RNA:DNA hybrids has implications for the mechanism of Ig somatic hypermutation

Abstract

The implications are discussed of recently published biochemical studies on ADAR-mediated A-to-I DNA and RNA deamination at RNA:DNA hybrids. The significance of these data are related to previous work on strand-biased and codon-context mutation signatures in B lymphocytes and cancer genomes. Those studies have established that there are two significant strand biases at A:T and G:C base pairs, A-site mutations exceed T-site mutations (A>>T) by 2.9 fold and G-site mutations exceed C-site mutations (G>>C) by 1.7 fold. Both these strand biases are inconsistent with alternative "DNA Deamination" mechanisms, yet are expected consequences of the RNA/RT-based "Reverse Transcriptase" mechanism of immunoglobulin (Ig) somatic hypermutation (SHM). The A-to-I DNA editing component at RNA:DNA hybrids that is likely to occur in Transcription Bubbles, while important, is of far lower A-to-I editing efficiency than in dsRNA substrates. The RNA moiety of RNA:DNA hybrids is also edited at similar lower frequencies relative to the editing rate at 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 for Ig SHM 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. It is concluded that the strand-biased somatic mutation patterns at both A:T and G:C base pairs in vivo are best interpreted by the sequential steps of the RNA/RT-based mechanism. Further, the direct DNA A-to-I deamination at Transcription Bubbles is expected to contribute to the T-to-C component of the strand-biased Ig SHM spectrum.

Keywords: A-to-I RNA and DNA editing; AID/APOBEC-deaminase oncogenesis; Codon-context mutations; DNA polymerase-η; Somatic hypermutation; Strand-biased mutations.