Seminars

Cells use a variety of well-conserved pathways to respond to perturbations of homeostasis or “cell stress”. Our studies have focused on pathways that respond to genotoxic stresses to preserve chromosome integrity and allow cells to return to homeostasis. We are particularly interested in how disease states alter the ability of cells to properly adapt to such stresses. Our recent work has focused on replication stress, which induces errors in sister chromatid resolution that in mammalian cells can give rise to micronuclei implicated in chromosomal rearrangements found in cancers. Several reports have led to the hypothesis that micronuclei activate autophagy as a way to eliminate these aberrant cell structures. To further examine this hypothesis, we have analyzed autophagy after replication stress in budding yeast mitosis. We find that replication stress induces nucleophagy through the formation of nuclear-vacuolar junctional that require the nuclear ER receptors Atg39 and Atg40, as well as the vacuolar protein, Vac8. Remarkably, we find that nucleolar proteins, but not chromatin per se, is targeted to the vacuole after transient replication stress. Elimination of this pathway alters the ability of cells to adapt their rDNA arrays to replication stress. In addition to examining the pathways that respond to genotoxic stress, we have also characterized a novel role for septins — cytoskeletal filaments that regulate integral membrane protein distribution — in limiting the autophagy program induced by nutrient deprivation as well as other forms of cell stress. Under these conditions, septins arrange at the cell cortex where they constrain trafficking of ER-derived membranes. The failure to limit autophagy in septin mutants allows cell survival in the short term but decreases cell survival in the long-term, potentially mimicking the evolution of cellular disease states.