Isolation of MLL1 Inhibitory RNA Aptamers

Ul-Haq, Asad; Jin, Ming Li; Jeong, Kwang Won; Kim, Hwan-Mook; Chun, Kwang-Hoon

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자료유형: 학술저널

저자정보: Ul-Haq, Asad (Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University) Jin, Ming Li (Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University) Jeong, Kwang Won (Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University) Kim, Hwan-Mook (Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University) Chun, Kwang-Hoon (Gachon Institute of Pharmaceutical Sciences, College of Pharmacy, Gachon University)

저널정보: 한국응용약물학회 Biomolecules & Therapeutics(구 응용약물학회지) Biomolecules & therapeutics 제27권 제2호

발행연도: 2019.1

수록면: 201 - 209 (9page)

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Mixed lineage leukemia proteins (MLL) are the key histone lysine methyltransferases that regulate expression of diverse genes. Aberrant activation of MLL promotes leukemia as well as solid tumors in humans, highlighting the urgent need for the development of an MLL inhibitor. We screened and isolated MLL1-binding ssRNAs using SELEX (${\underline{S}}ystemic$ ${\underline{E}}volution$ of ${\underline{L}}igands$ by ${\underline{E}}xponential$ enrichment) technology. When sequences in sub-libraries were obtained using next-generation sequencing (NGS), the most enriched aptamers-APT1 and APT2-represented about 30% and 26% of sub-library populations, respectively. Motif analysis of the top 50 sequences provided a highly conserved sequence: 5'-A[A/C][C/G][G/U][U/A]ACAGAGGG[U/A]GG[A/C] GAGUGGGU-3'. APT1, APT2, and APT5 embracing this motif generated secondary structures with similar topological characteristics. We found that APT1 and APT2 have a good binding activity and the analysis using mutated aptamer variants showed that the site information in the central region was critical for binding. In vitro enzyme activity assay showed that APT1 and APT2 had MLL1 inhibitory activity. Three-dimensional structure prediction of APT1-MLL1 complex indicates multiple weak interactions formed between MLL1 SET domain and APT1. Our study confirmed that NGS-assisted SELEX is an efficient tool for aptamer screening and that aptamers could be useful in diagnosis and treatment of MLL1-mediated diseases.

#Aptamers #SELEX #MLL1 #Next-generation sequencing #ssRNA

참고문헌 (34)

참고문헌 신청

Agostini F / 2013 / catRAPID omics : a web server for large-scale prediction of protein-RNA interactions / Bioinformatics 29:2928~2930

Ansari KI / 2013 / Histone methylase MLL1 has critical roles in tumor growth and angiogenesis and its knockdown suppresses tumor growth in vivo / Oncogene 32:3359~3370

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Bolshan Y / 2013 / Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction / ACS Med. Chem. Lett 4:353~357

Borkin D / 2015 / Pharmacologic inhibition of the Menin-MLL interaction blocks progression of MLL leukemia in vivo / Cancer Cell 27:589~602

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