Encyclopedia of Parallel Computing
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
... 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. Abbreviations used in this paper: Aag, alkyladenine DNA glycosylase; ADAR, Adenosine Deaminase that acts on RNA; AID, activation induced cytidine deaminase, a APOBEC family member, initiating via C-to-U lesions in ssDNA of class switch recombination (CSR) and somatic hypermutation (SHM) processes at somatically rearranged Ig V(D)J gene loci, and known to activate cytidine mutagenic deamination during transcription in other somatic tissues, particularly in cancer; APOBEC family, generic abbreviation for the deoxyribonucleic acid, or dC-to-dU, deaminase family (APOBEC3 A, B, C, D, F, G, H) similar in DNA sequence to the "apolipoprotein B RNA editor" APOBEC1, and known to activate mutagenic cytidine deamination during transcription in somatic tissues, particularly in cancer; AP, an Abasic, or apurinic/apyrimidinic, site; APE, AP endonuclease; A-to-I, adenosine-to-inosine RNA editing; BER, base excision repair; dA, deoxyadenosine; dA-to-dI, deoxyadenosine to deoxyinosine DNA editing; dC, deoxycytosine; Deaminase, catalytic domain in ADAR and AID/APOBEC enzymes; Ig-SHM-like response, strand-biased somatic mutation patterns similar to that observed in Ig SHM; MMR, mismatch repair; Motif, 4 to 6 nucleotide (N) sequence defining specificity of deaminase targeting; MSH2-MSH6, MutSa heterodimer recognising mispaired bases in DNA duplex; NTS, the non-transcribed, or "Top", 5' to 3' strand; Pol-h or DNA polymerase-h (eta); RNA Pol II, RNA Polymerase II; rA, adenosine in RNA; RT, reverse transcriptase; RT-Pol-h, reverse transcriptase activity displayed by Pol-h; SHM, somatic hypermutation; T, Thymine; TS, the transcribed, or "Bottom", 3' to 5' strand, in context of a Transcription Bubble; TSM, targeted somatic mutations : the process of targeting C and A nucleotides for deamination in actively transcribed genes that results in a dominant type of mutation caused by a deaminase binding domain (DBD) or an Inferred-DBD at a particular codon position; TSRT, target site reverse transcription; U, uracil; UNG, uracyl DNA glycosylase involved in BER at dU sites in DNA resulting in either an Abasic site (AP) or APE-mediated ssDNA nicks (above); V[D]J, generic symbol for a rearranged immunoglobulin (or T cell receptor, TCR) variable region gene in the Adaptive Immune System; W, weak base pair involving A or U/T; Y, pyrimidines T/U or C.