Recruitment of the m6A/Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48

Nabeel-Shah, S.; Pu, S.; Burke, G. L.; Ahmed, N.; Braunschweig, U.; Farhangmehr, S.; Lee, H.; Wu, M.; Ni, Z.; Tang, H.; Zhong, G.; Marcon, E.; Zhang, Z.; Blencowe, B. J.; Greenblatt, J. F.

doi:10.1101/2024.01.15.575768

bioRxiv · 10.1101/2024.01.15.575768

Recruitment of the m6A/Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48

Nabeel-Shah, S.·Pu, S.·Burke, G. L.·Ahmed, N.·Braunschweig, U.·Farhangmehr, S.·Lee, H.·Wu, M.·Ni, Z.·Tang, H.·Zhong, G.·Marcon, E.·Zhang, Z.·Blencowe, B. J.·Greenblatt, J. F.

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Abstract

N6-methyladenosine (m6A), the most abundant internal modification on eukaryotic mRNA, and N6, 2'-O-dimethyladenosine (m6Am), are epitranscriptomic marks that function in multiple aspects of posttranscriptional regulation. Fat mass and obesity-associated protein (FTO) can remove both m6A and m6Am; however, little is known about how FTO achieves its substrate selectivity. Here, we demonstrate that ZBTB48, a C2H2-zinc finger protein that functions in telomere maintenance, associates with FTO and binds both mRNA and the telomere-associated regulatory RNA TERRA to regulate the functional interactions of FTO with target transcripts. Specifically, depletion of ZBTB48 affects targeting of FTO to sites of m6A/m6Am modification, changes cellular m6A/m6Am levels and, consequently, alters decay rates of target RNAs. ZBTB48 ablation also accelerates growth of HCT-116 colorectal cancer cells and modulates FTO- dependent regulation of Metastasis-associated protein 1 (MTA1) transcripts by controlling the binding to MTA1 mRNA of the m6A reader IGF2BP2. Our findings thus uncover a previously unknown mechanism of posttranscriptional regulation in which ZBTB48 co-ordinates RNA- binding of the m6A/m6Am demethylase FTO to control expression of its target RNAs.

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Nabeel-Shah, S., Pu, S., Burke, G. L., Ahmed, N., Braunschweig, U., Farhangmehr, S., Lee, H., Wu, M., Ni, Z., Tang, H., Zhong, G., Marcon, E., Zhang, Z., Blencowe, B. J., Greenblatt, J. F.. 2024-01-16. Recruitment of the m6A/Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48. https://doi.org/10.1101/2024.01.15.575768

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