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Recruitment of the m6A/m6Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2024年9月19日

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  • Syed Nabeel-Shah,
  • Shuye Pu,
  • Giovanni L. Burke,
  • Nujhat Ahmed,
  • Ulrich Braunschweig,
  • Shaghayegh Farhangmehr,
  • Hyunmin Lee,
  • Mingkun Wu,
  • Zuyao Ni,
  • Hua Tang,
  • Guoqing Zhong,
  • Edyta Marcon,
  • Zhaolei Zhang,
  • Benjamin J. Blencowe,
  • Jack F. Greenblatt

摘要

Background

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.

Results

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.

Conclusions

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.