A Role for Non‐B DNA Forming Sequences in Mediating Microlesions Causing Human Inherited Disease. Issue 1 (2nd November 2015) - Kamat, Mihir Anant
Abstract : This is the first study assessing the extent to which four different types of non‐B DNA‐formingsequence direct, inverted, RY‐rich mirror repeats, and G‐quartets capable of slipped, hairpin/cruciform, triplex, and G‐quadruplex structure formation, respectively, may be involved in mediating different types of micro‐lesion causing (or associated with) human inherited disease. Novel mechanisms of mutagenesis, based on either the formation or resolution of non‐B DNA structures, have been proposed providing support for a role for non‐B DNA structures in mutagenesis. ABSTRACT: Missense/nonsense mutations and microdeletions/microinsertions (<21 bp) represent ∼76% of all mutations causing human inherited disease, and their occurrence has been associated with sequence motifs (direct, inverted, and mirror repeats; G‐quartets) capable of adopting non‐B DNA structures. We found that a significant proportion (∼21%) of both microdeletions and microinsertions occur within direct repeats, and are explicable by slipped misalignment. A novel mutational mechanism, DNA triplex formation followed by DNA repair, may explain ∼5% of microdeletions and microinsertions at mirror repeats. Further, G‐quartets, direct, and inverted repeats also appear to play a prominent role in mediating missense mutations, whereas only direct and inverted repeats mediate nonsense mutations. We suggest a mutational mechanism involving slipped strand mispairing, slipped structure formation, and DNA repair, to explain ∼15% of missense and ∼12% of nonsense mutations yielding perfect direct repeats from imperfect repeats, or the extension of existing direct repeats. Similar proportions of missense and nonsense mutations were explicable by hairpin/loop formation and DNA repair, yielding perfect inverted repeats from imperfect repeats. We also propose a model for single base‐pair substitution based on one‐electron oxidation reactions at G‐quadruplex DNA. Overall, the proposed mechanisms provide support for a role for non‐B DNA structures in human gene mutagenesis.