Electronic versions



  • Rita Cha
  • Isaac Corcoles Saez
  • Kangzhen Dong
  • Anthony Johnson
  • Erik Waskiewicz
  • Michael Costanzo
    University of Toronto, Canada
  • Charles Boone
    University of Toronto, Canada
Unlike most checkpoint proteins, Mec1, an ATM/ATR kinase, is essential. We utilized mec1-4, a missense allele (E2130K) which 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 analogue, 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 signalling network, Rad53CHK1, Dun1, and Sml1, also impact survival in response to proteotoxic stress. Activation of autophagy or sml1 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.


  • ATM, ATR, Mec1, proteostasis, checkpoint
Original languageEnglish
Pages (from-to)495-503
JournalDevelopmental Cell
Issue number4
Early online date20 Aug 2018
Publication statusPublished - 20 Aug 2018

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