Non‐B DNA Structure and Mutations Causing Human Genetic Disease

Cardiff University, Institute of Medical Genetics, School of Medicine, Cardiff, UK
DOI: 10.1002/9780470015902.a0022657 In book: eLS
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Available from: Albino Bacolla, Jun 22, 2014
    • "This notwithstanding, the significantly greater association of direct repeats with microlesions , relative to the other types of repeat, may reflect their independence of pH and other parameters. Indeed, whereas a hairpin structure would only require Na + ions for stabilization, triplex structures may be further stabilized by other factors, such as acidic pH, Mg 2+ and spermine and spermidine ions (Raghavan and Lieber, 2007; Bacolla et al., 2010; Sharma, 2011) whereas G-quadruplexes are best stabilized by K + ions (Chen and Yang, 2012). "
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    ABSTRACT: Missense/nonsense mutations and micro-deletions/micro-insertions (<21bp) 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 micro-deletions and micro-insertions 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 micro-deletions and micro-insertions 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. This article is protected by copyright. All rights reserved.
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    ABSTRACT: Background: RNA:DNA hybrids represent a non-canonical nucleic acid structure that has been associated with a range of human diseases and potential transcriptional regulatory functions. Mapping of RNA:DNA hybrids in human cells reveals them to have a number of characteristics that give insights into their functions. Results: We find RNA:DNA hybrids to occupy millions of base pairs in the human genome. A directional sequencing approach shows the RNA component of the RNA:DNA hybrid to be purine-rich, indicating a thermodynamic contribution to their in vivo stability. The RNA:DNA hybrids are enriched at loci with decreased DNA methylation and increased DNase hypersensitivity, and within larger domains with characteristics of heterochromatin formation, indicating potential transcriptional regulatory properties. Mass spectrometry studies of chromatin at RNA:DNA hybrids shows the presence of the ILF2 and ILF3 transcription factors, supporting a model of certain transcription factors binding preferentially to the RNA:DNA conformation. Conclusions: Overall, there is little to indicate a dependence for RNA:DNA hybrids forming co-transcriptionally, with results from the ribosomal DNA repeat unit instead supporting the intriguing model of RNA generating these structures in trans. The results of the study indicate heterogeneous functions of these genomic elements and new insights into their formation and stability in vivo.
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