Computational analyses show A-to-G mutations correlate with nascent mRNA hairpins at somatic hypermutation hotspots

Edward J. Steele*, Robyn A. Lindley, Jiayu Wen, Georg F. Weiller

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    35 Citations (Scopus)

    Abstract

    Activation-induced cytidine deaminase (AID) initiates Phase I somatic hypermutation (SHM) of antibody genes by deaminating deoxy-cytosine to deoxy-uracil (C-to-U). These lesions trigger Phase II, a poorly understood process of error-prone repair targeting A-T pairs by DNA polymerase η (Pol η). Since Pol η is also a reverse transcriptase, Phase II could involve copying off RNA as well as DNA templates. We explore this idea further since in an RNA-based pathway it is conceivable that adenosine-to-inosine (A-to-I) RNA editing causes A-to-G transitions since I like G pairs with C. Adenosine deaminases (ADARs) are known to preferentially edit A nucleotides that are preceded by an A or U (W) in double-stranded RNA substrates. On this assumption and using a theoretical bioinformatics approach we show that a significant and specific correlation (P < 0.002) exists between the frequency of WA-to-WG mutations and the number of mRNA hairpins that could potentially form at the mutation site. This implies roles for both RNA editing and reverse transcription during SHM in vivo and suggests definitive genetic experiments targeting the appropriate ADAR1 isoform (γINF-ADAR1) and/or Ig pre-mRNA templates.

    Original languageEnglish
    Pages (from-to)1346-1363
    Number of pages18
    JournalDNA Repair
    Volume5
    Issue number11
    DOIs
    Publication statusPublished - 8 Nov 2006

    Fingerprint

    Dive into the research topics of 'Computational analyses show A-to-G mutations correlate with nascent mRNA hairpins at somatic hypermutation hotspots'. Together they form a unique fingerprint.

    Cite this