ATM and ATR are master regulators of the DNA damage response linked to cancer, neurodegeneration, and accelerated ageing. We find that inactivation of Mec1, an essential budding yeast ATM/ATR protein, leads to widespread protein aggregation and cell death in response to three different types of proteotoxic stresses; heat, Huntingtin (HTT), the aggregation prone Huntington’s disease protein, andazetidine 2 carboxylic acid (AZC), a proline analogue that induces protein misfolding. Conditions that activate protein catabolism (e.g. activation of autophagy) or impede protein anabolism (e.g. cycloheximide [CHX] or deletion of genes involved translation) rescues the lethality via aggregate-resolution. Inactivation of Rad53- or Dun1- kinases, the two key components of the Mec1 DNA damage checkpoint response, confers distinct sensitivity profiles: rad53K277A confers sensitivity to AZC, HTT, and CHX; in contrast, dun1Δconfers sensitive only to AZC and HTT but robust resistance to CHX. We also find that Sml1, an inhibitor of ribonucleotide reductase (RNR), which undergoes Mec1-Rad53-Dun1 dependent degradation in response to DNA damage is maintained in response to proteotoxic stress. Taken together, these results unveil a new function of Mec1 in mediating cellular response to perturbation in protein homeostasis. We propose that Mec1 is a versatile signal transduction protein that promotes resistance to both genotoxic and proteotoxic stresses via distinct mechanisms.

  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.

Article metrics loading...

Loading full text...

Full text loading...


Most cited this month Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error