During growth with abundant methionine, MET gene expression is repressed through a Met4-attached K48-linked ubiquitin chain. The K48-ubiquitin chain interacts intramolecularly with the K48-selective tandem UBD in Met4 and prevents mediator recruitment to the tandem UBD/transactivation region. The system is activated when cells experience methionine limitation, which induces a change in topology of the ubiquitin chain attached to K163 in Met4. The new topology could be a homotypic K11 chain (A), a branched K48/K11 chain (B), or a heterotypic K48/K11 chain (C). After initiation of activation through changes in ubiquitin chain topology, Met4 deubiquitylation completes the activation process.