A G-quadruplex-forming RNA aptamer binds to the MTG8 TAFH domain and dissociates the leukemic AML1-MTG8 fusion protein from DNA.

Junichi Fukunaga, Yusuke Nomura, Yoichiro Tanaka, Hidetaka Torigoe, Yoshikazu Nakamura, Taiichi Sakamoto, Tomoko Kozu

FEBS letters 2020 Nov

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MTG8 (RUNX1T1) is a fusion partner of AML1 (RUNX1) in the leukemic chromosome translocation t(8;21). The AML1-MTG8 fusion gene encodes a chimeric transcription factor. One of the highly conserved domains of MTG8 is TAFH which possesses homology with human TAF4 [TATA-box binding protein-associated factor]. To obtain specific inhibitors of the AML1-MTG8 fusion protein, we isolated RNA aptamers against the MTG8 TAFH domain using systematic evolution of ligands by exponential enrichment. All TAF aptamers contained guanine-rich sequences. Analyses of a TAF aptamer by NMR, CD, and mutagenesis revealed that it forms a parallel G-quadruplex structure in the presence of K+ . Furthermore, the aptamer could bind to the AML1-MTG8 fusion protein and dissociate the AML1-MTG8/DNA complex, suggesting that it can inhibit the dominant negative effects of AML1-MTG8 against normal AML1 function and serve as a potential therapeutic agent for leukemia. © 2020 Federation of European Biochemical Societies.

Citation

Junichi Fukunaga, Yusuke Nomura, Yoichiro Tanaka, Hidetaka Torigoe, Yoshikazu Nakamura, Taiichi Sakamoto, Tomoko Kozu. A G-quadruplex-forming RNA aptamer binds to the MTG8 TAFH domain and dissociates the leukemic AML1-MTG8 fusion protein from DNA. FEBS letters. 2020 Nov;594(21):3477-3489