ZNF121 recruits YTHDF2 to modulate mRNA stability

Abstract N6-methyladenosine (m6A) is the most abundant internal modification in mRNA and has been shown to regulate gene expression through the binding of specific reader proteins, such as YTHDF2, which promotes mRNA decay. Previous studies indicate that YTHDF2 has relatively weak intrinsic RNA-binding affinity, suggesting that additional factors may facilitate its association with target transcripts. Here, we show that the C2H2-Zinc Finger protein, ZNF121, binds mRNA in cells and physically interacts with YTHDF2 in the cytoplasm. We demonstrate that approximately 80% of ZNF121-bound mRNAs are also YTHDF2 targets, and that their binding sites highly correlate with each other. Loss of ZNF121 impairs YTHDF2 binding to shared targets and increases their stability, independent of the presence of m6A modifications. Moreover, co-regulated transcripts are enriched for cell-cycle–related pathways, and ZNF121 depletion leads to elevated expression of the oncogene MDM2, implicating ZNF121 in growth control and the DNA damage response. Our findings identify ZNF121 as a cofactor that enhances YTHDF2-mediated mRNA regulation and reveal a previously unknown layer of control in mRNA decay. Competing Interest Statement The authors have declared no competing interest.