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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
2019-12-09
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http://instance.metastore.ingenta.com/content/journal/acmi/10.1099/acmi.byg2019.po0007
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