Crystal Structure Of An i-Motif From The HRAS Oncogene Promoter

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Angewandte Chemie International Edition


An i-motif is a non-canonical DNA structure implicated in gene regulation and linked to cancers. The C-rich strand of the HRAS oncogene, 5′-CGCCCGTGCCCTGCGCCCGCAACCCGA-3′ (herein referred to as iHRAS), forms an i-motif in vitro but its exact structure was unknown. HRAS is a member of the RAS proto-oncogene family. About 19% of US cancer patients carry mutations in RAS genes. We solved the structure of iHRAS at 1.77 Å resolution. The structure reveals that iHRAS folds into a double hairpin. The two double hairpins associate in an antiparallel fashion, forming an i-motif dimer capped by two loops on each end and linked by a connecting region. Six C−C⁺ base pairs form each i-motif core, and the core regions are extended by a G−G base pair and a cytosine stacking. Extensive canonical and non-canonical base pairing and stacking stabilizes the connecting region and loops. The iHRAS structure is the first atomic resolution structure of an i-motif from a human oncogene. This structure sheds light on i-motifs folding and function in the cell.


Dimers, Gene Regulation, Non-Canonical Base Pairing, X-Ray Crystallography, i-Motifs

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