Mec1ATM/ATR is a multifaceted protein kinase promoting cellular response to genotoxic stress and perturbation in protein homeostasis Open Access

Abstract

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.

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/content/journal/acmi/10.1099/acmi.byg2019.po0007
2019-11-01
2024-03-28
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