Aggregation of the Whi3 protein, not loss of heterochromatin, causes sterility in old yeast cells

Abstract

In yeast, heterochromatin silencing is reported to decline in aging mother cells, causing sterility in old cells. This process is thought to reflect a decrease in the activity of the NAD⁺ (oxidized nicotinamide adenine dinucleotide)-dependent deacetylase Sir2. We tested whether Sir2 becomes nonfunctional gradually or precipitously during aging. Unexpectedly, silencing of the heterochromatic <i>HML</i> and <i>HMR</i> loci was not lost during aging. Old cells could initiate a mating response; however, they were less sensitive to mating pheromone than were young cells because of age-dependent aggregation of Whi3, an RNA-binding protein controlling S-phase entry. Removing the polyglutamine domain of Whi3 restored the pheromone sensitivity of old cells. We propose that aging phenotypes previously attributed to loss of heterochromatin silencing are instead caused by aggregation of the Whi3 cell cycle regulator.