Recent studies indicate that i-DNA, a four-stranded cytosine-rich DNA also known as the i-motif, is actually formed in vivo; however, a systematic study on sequence effects on stability has been missing. Herein, an unprecedented number of different sequences (271) bearing four runs of 3-6 cytosines with different spacer lengths has been tested. While i-DNA stability is nearly independent on total spacer length, the central spacer plays a special role on stability. Stability also depends on the length of the C-tracts at both acidic and neutral pHs. This study provides a global picture on i-DNA stability thanks to the large size of the introduced data set; it reveals unexpected features and allows to conclude that determinants of i-DNA stability do not mirror those of G-quadruplexes. Our results illustrate the structural roles of loops and C-tracts on i-DNA stability, confirm its formation in cells, and allow establishing rules to predict its stability.

ARNA Laboratory Université de Bordeaux INSERM U 1212 CNRS UMR5320 IECB 33607 Pessac France

Central European Institute of Technology Masaryk University 62500 Brno Czech Republic

IBENS Ecole Normale Supérieure CNRS INSERM PSL Research University 75005 Paris France

Laboratoire d'Optique et Biosciences Ecole Polytechnique CNRS INSERM Institut Polytechnique de Paris 91128 Palaiseau France

MRC WIMM Centre for Computational Biology MRC Weatherall Institute of Molecular Medicine Radcliffe Department of Medicine University of Oxford Oxford OX3 9DS UK

State Key Laboratory of Analytical Chemistry for Life Science School of Chemistry and Chemical Engineering Nanjing University Nanjing 210023 China

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In-cell NMR suggests that DNA i-motif levels are strongly depleted in living human cells

DNA i-motif formation at neutral pH is driven by kinetic partitioning

Towards Profiling of the G-Quadruplex Targeting Drugs in the Living Human Cells Using NMR Spectroscopy