Targeted O-GlcNAcylation enables functional rewiring of c-Myc.

Abstract

Chemically induced proximity has transformed targeted protein degradation but has been applied far less extensively to directly reprogram protein function through post-translational modification (PTM). Here, we develop an O-GlcNAcylation-targeting Chimera (OGTAC) that recruits O-GlcNAc transferase (OGT) to the oncogenic transcription factor c-Myc, enabling targeted O-GlcNAcylation in living cells without globally perturbing cellular O-GlcNAcylation. OGTAC suppresses HeLa cell proliferation, rewires c-Myc genomic occupancy, and reprograms expression of the downstream oncogene MALAT1 in an O-GlcNAcylation-dependent manner. By selectively modulating the regulatory state of c-Myc rather than its abundance, OGTAC establishes targeted O-GlcNAcylation as a chemically induced proximity strategy for functional rewiring of transcription factors. More broadly, this work expands proximity-induced protein regulation beyond degradation to programmable PTM.