Crystal Structure of an i‐Motif from the HRAS Oncogene Promoter

Li, Kevin S.; Jordan, Deondre; Lin, Linda Y.; McCarthy, Sawyer E.; Schneekloth, Jr., John S.; Yatsunyk, Liliya A.

doi:10.1002/ange.202301666

Title: Crystal Structure of an i‐Motif from the HRAS Oncogene Promoter

Journal Article · 25 April 2023 · Angewandte Chemie

DOI: https://doi.org/10.1002/ange.202301666 · OSTI ID:1971416

Li, Kevin S. ^[1]; Jordan, Deondre ^[1];

^[1];

^[1]; Schneekloth, Jr., John S. ^[2];

^[1]

Department Chemistry and Biochemistry Swarthmore College 500 College Ave Swarthmore PA 19081 USA
Chemical Biology Laboratory National Cancer Institute National Institute of Health Frederick MD 21702 USA

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′‐CG CCC GTG CCC TGCG CCC GCAA CCC 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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Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1971416

Alternate ID(s):: OSTI ID: 1983499

Journal Information:: Angewandte Chemie, Journal Name: Angewandte Chemie Vol. 135 Journal Issue: 26; ISSN 0044-8249

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: Germany

Language:: English

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