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- W2890165403 endingPage "9950" @default.
- W2890165403 startingPage "9932" @default.
- W2890165403 abstract "c-MYC proto-oncogene harbours a transcription-inhibitory quadruplex-forming scaffold (Pu27) upstream P1 promoter providing anti-neoplastic therapeutic target. Previous reports showed the binding profile of human Cathelicidin peptide (LL37) and telomeric G-quadruplex. Here, we truncated the quadruplex-binding domain of LL37 to prepare a small library of peptides through site-specific amino acid substitution. We investigated the intracellular selectivity of peptides for Pu27 over other oncogenic quadruplexes and their role in c-MYC promoter repression by dual-luciferase assays. We analysed their thermodynamics of binding reactions with c-MYC quadruplex isomers (Pu27, Myc22, Pu19) by Isothermal Titration Calorimetry. We discussed how amino acid substitutions and peptide helicity enhanced/weakened their affinities for c-MYC quadruplexes and characterized specific non-covalent inter-residual interactions determining their selectivity. Solution NMR structure indicated that KR12C, the best peptide candidate, selectively stabilized the 5'-propeller loop of c-MYC quadruplex by arginine-driven electrostatic-interactions at the sugar-phosphate backbone while KR12A peptide destabilized the quadruplex inducing a single-stranded hairpin-like conformation. Chromatin immunoprecipitations envisaged that KR12C and KR12A depleted and enriched Sp1 and NM23-H2 (Nucleoside diphosphate kinase) occupancy at Pu27 respectively supporting their regulation in stabilizing and unfolding c-MYC quadruplex in MCF-7 cells. We deciphered that selective arresting of c-MYC transcription by KR12C triggered apoptotic-signalling pathway via VEGF-A-BCL-2 axis." @default.
- W2890165403 created "2018-09-27" @default.
- W2890165403 creator A5027555519 @default.
- W2890165403 creator A5032112832 @default.
- W2890165403 creator A5051826895 @default.
- W2890165403 creator A5060364973 @default.
- W2890165403 creator A5070259439 @default.
- W2890165403 creator A5086757068 @default.
- W2890165403 date "2018-09-17" @default.
- W2890165403 modified "2023-10-15" @default.
- W2890165403 title "Site-specific amino acid substitution in dodecameric peptides determines the stability and unfolding of<i>c-MYC</i>quadruplex promoting apoptosis in cancer cells" @default.
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