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 sml1Δ 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.

• PMID: 30130531
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Journal Article | Research Support, Non-U.S. Gov't

Authors

Corcoles-Saez I, Dong K, Johnson AL, Waskiewicz E, Costanzo M, Boone C, Cha RS

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