i-Motif formation and spontaneous deletions in human cells

Martella, Marianna, Pichiorri, Flavia, Chikhale, Rupesh V. ORCID: https://orcid.org/0000-0001-5622-3981, Abdelhamid, Mahmoud A. S., Waller, Zoë A. E. and Smith, Steven S. (2022) i-Motif formation and spontaneous deletions in human cells. Nucleic Acids Research, 50 (6). 3445–3455. ISSN 0305-1048

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Abstract

Concatemers of d(TCCC) that were first detected through their association with deletions at the RACK7 locus, are widespread throughout the human genome. Circular dichroism spectra show that d(GGGA)n sequences form G-quadruplexes when n > 3, while i-motif structures form at d(TCCC)n sequences at neutral pH when n ≥ 7 in vitro. In the PC3 cell line, deletions are observed only when the d(TCCC)n variant is long enough to form significant levels of unresolved i-motif structure at neutral pH. The presence of an unresolved i-motif at a representative d(TCCC)n element at RACK7 was suggested by experiments showing that that the region containing the d(TCCC)9 element was susceptible to bisulfite attack in native DNA and that d(TCCC)9 oligo formed an i-motif structure at neutral pH. This in turn suggested that that the i-motif present at this site in native DNA must be susceptible to bisulfite mediated deamination even though it is a closed structure. Bisulfite deamination of the i-motif structure in the model oligodeoxynucleotide was confirmed using mass spectrometry analysis. We conclude that while G-quadruplex formation may contribute to spontaneous mutation at these sites, deletions actually require the potential for i-motif to form and remain unresolved at neutral pH.

Item Type:	Article
Additional Information:	Funding: Biotechnology and Biological Sciences Research Council [BB/L02229X/1 to Z.A.E.W, 5R01-CA102521 to S.S.S.] from the U.S. National Cancer Institute of the National Institutes of Health; Ensign Foundation; Diabetes UK [18/0005820 to R.V.C.]; research reported in this publication also included work performed in the Integrative Genomics and Bioinformatics Core supported by the National Cancer Institute of the National Institutes of Health [P30CA033572]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding for open access charge: Institutional Funds.
Faculty \ School:	Faculty of Science > School of Pharmacy (former - to 2024)
Related URLs:	https://academic.oup.com/nar/advance-art...
Depositing User:	LivePure Connector
Date Deposited:	31 Mar 2022 09:31
Last Modified:	25 Sep 2024 16:17
URI:	https://ueaeprints.uea.ac.uk/id/eprint/84375
DOI:	10.1093/nar/gkac158

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