A role for non-B DNA forming sequences in mediating microlesions causing human inherited disease

Kamat, Mihir Anant, Bacolla, Albino, Cooper, David Neil ORCID: https://orcid.org/0000-0002-8943-8484 and Chuzhanova, Nadia 2015. A role for non-B DNA forming sequences in mediating microlesions causing human inherited disease. Human Mutation 37 (1) , pp. 65-73. 10.1002/humu.22917

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Subjects:	Q Science > QR Microbiology > QR180 Immunology R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	Wiley-Blackwell
ISSN:	10597794
Date of Acceptance:	22 September 2015
Last Modified:	31 Oct 2022 10:17
URI:	https://orca.cardiff.ac.uk/id/eprint/84270

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