Essential Function of Mec1, the Budding Yeast ATM/ATR Checkpoint-Response Kinase, in Protein Homeostasis

Unlike most checkpoint proteins, Mec1, an ATM/ATR kinase, is essential. We utilized mec1-4, a missense allele (E2130K) that confers diminished kinase activity, to interrogate the question. Unbiased screen for genetic interactors of mec1-4 identified numerous genes involved in proteostasis. mec1-4 confers sensitivity to heat, an amino acid analog, and Htt103Q, an aggregation-prone model peptide of Huntingtin. Oppositely, mec1-4 confers resistance to cycloheximide, a translation inhibitor. In response to heat, mec1-4 leads to widespread protein aggregation and cell death. Key components of the Mec1 signaling network, Rad53(CHK1), Dun1, and Sml1, also impact survival in response to proteotoxic stress. Activation of autophagy or sml1D promotes aggregate resolution and rescues mec1-4 lethality. These findings show that proteostasis is a fundamental function of Mec1 and that Mec1 is likely to utilize its checkpoint response network to mediate resistance to proteotoxic stress, a role that may be conserved from yeast to mammalian cells.