Recruitment of the m 6 A/m6Am demethylase FTO to target RNAs by the telomeric zinc finger protein ZBTB48.

Autor: Nabeel-Shah S; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Canada., Pu S; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada., Burke GL; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Canada., Ahmed N; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Canada., Braunschweig U; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada., Farhangmehr S; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Canada., Lee H; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada.; Department of Computer Sciences, University of Toronto, Toronto, M5S 1A8, Canada., Wu M; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Canada., Ni Z; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada., Tang H; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada., Zhong G; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada., Marcon E; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada.; Department of laboratory Medicine and Pathobiology, University of Toronto, Toronto, M5S 1A8, Canada., Zhang Z; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Canada.; Department of Computer Sciences, University of Toronto, Toronto, M5S 1A8, Canada., Blencowe BJ; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada.; Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Canada., Greenblatt JF; Donnelly Centre, University of Toronto, Toronto, M5S 3E1, Canada. jack.greenblatt@utoronto.ca.; Department of Molecular Genetics, University of Toronto, Toronto, M5S 1A8, Canada. jack.greenblatt@utoronto.ca.
Jazyk: angličtina
Zdroj: Genome biology [Genome Biol] 2024 Sep 19; Vol. 25 (1), pp. 246. Date of Electronic Publication: 2024 Sep 19.
DOI: 10.1186/s13059-024-03392-7
Abstrakt: 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 m 6 A 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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