ZNF121 recruits YTHDF2 to modulate mRNA stability

N⁶-methyladenosine (m6A) is the most abundant mRNA modification, regulating gene expression through binding of reader proteins, such as YTHDF2, which promote mRNA decay. Previous studies indicate YTHDF2 has relatively weak intrinsic RNA-binding affinity, suggesting additional factors may facilitate RNA binding. 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 ∼80% of ZNF121-bound mRNAs are also YTHDF2 targets, and that their binding sites are highly correlated. Loss of ZNF121 impairs YTHDF2 binding to shared targets, mostly independent of m6A, increasing stability of a subset of targets. Co-regulated transcripts are enriched for cell-cycle-related pathways, and ZNF121 depletion elevates 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, highlighting a different mechanism for YTHDF2 in regulating mRNA decay.