A pathway of targeted autophagy is induced by DNA damage in budding yeast

Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):E1158-E1167. doi: 10.1073/pnas.1614364114. Epub 2017 Feb 2.

Abstract

Autophagy plays a central role in the DNA damage response (DDR) by controlling the levels of various DNA repair and checkpoint proteins; however, how the DDR communicates with the autophagy pathway remains unknown. Using budding yeast, we demonstrate that global genotoxic damage or even a single unrepaired double-strand break (DSB) initiates a previously undescribed and selective pathway of autophagy that we term genotoxin-induced targeted autophagy (GTA). GTA requires the action primarily of Mec1/ATR and Rad53/CHEK2 checkpoint kinases, in part via transcriptional up-regulation of central autophagy proteins. GTA is distinct from starvation-induced autophagy. GTA requires Atg11, a central component of the selective autophagy machinery, but is different from previously described autophagy pathways. By screening a collection of ∼6,000 yeast mutants, we identified genes that control GTA but do not significantly affect rapamycin-induced autophagy. Overall, our findings establish a pathway of autophagy specific to the DNA damage response.

Keywords: ATM kinase; ATR kinase; DNA damage; autophagy; budding yeast.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy / genetics*
  • Autophagy-Related Proteins / genetics
  • Autophagy-Related Proteins / metabolism
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Checkpoint Kinase 2 / genetics
  • Checkpoint Kinase 2 / metabolism
  • DNA Breaks, Double-Stranded*
  • DNA Damage*
  • DNA Repair
  • DNA, Fungal / genetics
  • DNA, Fungal / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction / genetics*
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism

Substances

  • Atg11 protein, S cerevisiae
  • Autophagy-Related Proteins
  • Cell Cycle Proteins
  • DNA, Fungal
  • Intracellular Signaling Peptides and Proteins
  • Saccharomyces cerevisiae Proteins
  • Vesicular Transport Proteins
  • Checkpoint Kinase 2
  • MEC1 protein, S cerevisiae
  • Protein Serine-Threonine Kinases
  • RAD53 protein, S cerevisiae