ZNF121 recruits YTHDF2 to modulate mRNA stability
RNA contains over 100 different chemical modifications. The most abundant mRNA modification, m6A, is bound by various reader proteins, which elicit specific effects on mRNA metabolism. One such reader protein, YTHDF2, recruits the mRNA decay machinery to target transcripts. YTHDF2 exhibits a weak mRNA binding affinity, and we hypothesized that protein-protein interactions might enhance its binding to targeted mRNAs. We show that the C2H2-Zinc Finger protein, ZNF121, binds to YTHDF2 in the cytoplasm and that ~80% of the mRNA targets of ZNF121 are also YTHDF2 targets. The mRNA binding sites of ZNF121 and YTHDF2 are correlated, and the loss of ZNF121 results in impaired binding of YTHDF2 to, and increased stability of, shared mRNA targets, regardless of whether m6A sites are present. Many mRNA targets bound by ZNF121 and YTHDF2 are enriched for cell cycle pathways. Further, we show that the deletion of ZNF121 results in increased abundance of MDM2, implicating ZNF121 in growth control and the DNA damage response.
RNA contains over 100 different chemical modifications. The most abundant mRNA modification, m6A, is bound by various reader proteins, which elicit specific effects on mRNA metabolism. One such reader protein, YTHDF2, recruits the mRNA decay machinery to target transcripts. YTHDF2 exhibits a weak mRNA binding affinity, and we hypothesized that protein-protein interactions might enhance its binding to targeted mRNAs. We show that the C2H2-Zinc Finger protein, ZNF121, binds to YTHDF2 in the cytoplasm and that ~80% of the mRNA targets of ZNF121 are also YTHDF2 targets. The mRNA binding sites of ZNF121 and YTHDF2 are correlated, and the loss of ZNF121 results in impaired binding of YTHDF2 to, and increased stability of, shared mRNA targets, regardless of whether m6A sites are present. Many mRNA targets bound by ZNF121 and YTHDF2 are enriched for cell cycle pathways. Further, we show that the deletion of ZNF121 results in increased abundance of MDM2, implicating ZNF121 in growth control and the DNA damage response.
University of Toronto