Esc1-mediated anchoring regulates telomere clustering in response to metabolic changes

Spatial organization of budding yeast telomeres is highly dynamic and regulated by growth conditions. In rich medium, the 32 telomeres group in 3–5 perinuclear foci, whereas they assemble into a hypercluster located in the center of the nucleus in long-lived quiescent (Q) cells, contributing to their long-term viability. Here, we explore the mechanisms underlying this reorganization. We rule out Sir3-mediated changes in telomere–telomere interactions as the main driver of hypercluster formation. Instead, physical modeling predicts that telomere anchoring antagonizes telomere clustering. Consistent with this prediction, genetic analyses support a model in which telomere anchoring relies on two redundant pathways in rich medium. One depends on PKA activity and is rapidly inactivated upon glucose depletion, whereas the other is progressively lost during entry into quiescence via dephosphorylation of a single residue of the nuclear envelope–associated protein Esc1. Inactivation of both pathways releases telomeres from the nuclear envelope, resulting in hypercluster formation specifically in Q cells.