Crystal Structure of an i-Motif from the HRAS Oncogene Promoter |
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Authors: | Kevin S Li Deondre Jordan Linda Y Lin Sawyer E McCarthy Dr John S Schneekloth Jr Dr Liliya A Yatsunyk |
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Institution: | 1. Department Chemistry and Biochemistry, Swarthmore College, 500 College Ave, Swarthmore, PA 19081 USA;2. Chemical Biology Laboratory, National Cancer Institute, National Institute of Health, Frederick, MD 21702 USA |
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Abstract: | 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′-CGCCC GTGCCC TGCGCCC GCAACCC GA-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. |
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Keywords: | Dimers Gene Regulation Non-Canonical Base Pairing X-Ray Crystallography i-Motifs |
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