The study identifies a novel class of methylated histone H3 lysine 4 (H3K4) effector domains in the PHD domains of the ING family of tumor suppressor proteins. Specifically, the ING2 PHD domain robustly binds to trimethylated H3K4 (H3K4me3) and di-methylated H3K4 (H3K4me2), with higher affinity for H3K4me3. This binding is critical for ING2's interaction with the mSin3a–HDAC1 histone deacetylase complex, which is involved in gene repression. In response to DNA damage, the ING2 PHD domain stabilizes the mSin3a–HDAC1 complex at the promoters of proliferation genes, leading to active gene repression. The study also demonstrates that ING2's interaction with H3K4me3 is essential for its cellular functions, including sensitivity to genotoxic insults. These findings highlight the role of H3K4me3 in gene repression and suggest that ING2's PHD domain functions as a dual-specificity module, binding both phosphatidylinositol-5-phosphate (PtdIns(5)P) and H3K4me3, with both activities contributing to ING2's cellular functions.The study identifies a novel class of methylated histone H3 lysine 4 (H3K4) effector domains in the PHD domains of the ING family of tumor suppressor proteins. Specifically, the ING2 PHD domain robustly binds to trimethylated H3K4 (H3K4me3) and di-methylated H3K4 (H3K4me2), with higher affinity for H3K4me3. This binding is critical for ING2's interaction with the mSin3a–HDAC1 histone deacetylase complex, which is involved in gene repression. In response to DNA damage, the ING2 PHD domain stabilizes the mSin3a–HDAC1 complex at the promoters of proliferation genes, leading to active gene repression. The study also demonstrates that ING2's interaction with H3K4me3 is essential for its cellular functions, including sensitivity to genotoxic insults. These findings highlight the role of H3K4me3 in gene repression and suggest that ING2's PHD domain functions as a dual-specificity module, binding both phosphatidylinositol-5-phosphate (PtdIns(5)P) and H3K4me3, with both activities contributing to ING2's cellular functions.