Résumé
The nuclear envelope (NE), which encloses and shields the genome, is in continuity with the rest of the endoplasmic reticulum (ER), of which it is considered a specialized subdomain. In recent years, awareness has been raised about the possibility that problems affecting genome integrity may signal to the rest of the ER or that, reciprocally, challenges experienced by the ER could translate into functional / structural genome alterations. We take advantage of the very plastic NE of Saccharomyces cerevisiae to explore these concepts.We screened the effect on perinuclear ER (pnER) morphologies of a battery of classically used chemical genotoxins. We found that Methylmethane sulfonate (MMS), a DNA-alkylating agent, led to much deformed, flower-like nuclei of increased NE perimeter. A long, educated-guess search led us to learn that this deformation was neither dependent on the DNA Damage Response (DDR), which commands the cellular reaction to DNA harms; nor on the nuclear DNA damage itself. It did not relate to the cell cycle phase, to any collateral ability of the drug to alkylate other molecules or to a shunt of methyl groups towards the phospholipid synthesis pathway. Instead, we found that massive pnER deformations induced by MMS were due to enlarged contacts with the vacuole, the yeast lysosome-like organelle, and were decorated with extensive continuous and discontinuous patches of the ERlysosome tether Nvj1.Mechanistically, MMS mimics acute glucose depletion (AGD), a natural trigger of lysosome-ER contacts. However, in contrast to AGD-induced membrane interactions, which nucleate sterol synthesislimiting enzymes to warrant efficient cell recovery upon stress, MMS-triggered contacts are unproductive sinks that trap the cell in a dead-end, sterol-depleted status. As a consequence, MMS-treated cells become dramatically sensitive to mild statin treatment. Thus, MMS imposes a quiescence-like signal independent from its well-known DNA replication-halting activity. Together, we define the establishment of a pathological contact site and put forward the potential of defining dual molecules capable of targeting genome and ER transactions simultaneously, for more potent treatments, for example during chemotherapy.