Lysine methylation as a bidirectional switch

Lysine methylation is classically linked to chromatin, yet an expanding literature shows that methylation on non-histone proteins can directly program protein lifetime through the Ub-proteasome system (UPS). We define a lysine methylation bidirectional switch in which methyl marks can be wired to opposite outcomes, degradation (methyl-degrons) or stabilization (methyl-stabilizers) depending on interpreter availability, competitive occupancy, and post-translational modification (PTM) neighborhood context. We organize the field into two symmetric frameworks and, within each, distinguish direct mechanisms from reader-mediated mechanisms. Across curated examples, both Kme1 and Kme2 are bidirectional, enabling either fate depending on the wiring. However, Kme1 dominates the degron pathways, while Kme3 only supports stabilization. We highlight recurring modular architectures and extract hypothesis-generating features that bias methyl sites toward degron versus stabilizer functions. Finally, we outline chemical biology opportunities to read and program this bidirectional switch, including antibody-independent chemoproteomics, proximity approaches for targeted methyl-editing for degradation and/or stabilization.