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DNA damage checkpoint triggers autophagy to regulate the initiation of anaphase.

Budding yeast cells suffering a single unrepaired double-strand break (DSB) trigger the Mec1 (ATR)-dependent DNA damage response that causes them to arrest before anaphase for 12-15 h. Here we find that hyperactivation of the cytoplasm-to-vacuole (CVT) autophagy pathway causes the permanent G2/M arrest of cells with a single DSB that is reflected in the nuclear exclusion of both Esp1 and Pds1. Transient relocalization of Pds1 is also seen in wild-type cells lacking vacuolar protease activity after induction of a DSB. Arrest persists even as the DNA damage-dependent phosphorylation of Rad53 diminishes. Permanent arrest can be overcome by blocking autophagy, by deleting the vacuolar protease Prb1, or by driving Esp1 into the nucleus with a SV40 nuclear localization signal. Autophagy in response to DNA damage can be induced in three different ways: by deleting the Golgi-associated retrograde protein complex (GARP), by adding rapamycin, or by overexpression of a dominant ATG13-8SA mutation.

Pubmed ID: 23169651

Authors

  • Dotiwala F
  • Eapen VV
  • Harrison JC
  • Arbel-Eden A
  • Ranade V
  • Yoshida S
  • Haber JE

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

January 2, 2013

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM61766
  • Agency: NIGMS NIH HHS, Id: R01 GM061766

Mesh Terms

  • Active Transport, Cell Nucleus
  • Adaptor Proteins, Signal Transducing
  • Anaphase
  • Autophagy
  • Blotting, Western
  • Cell Cycle Checkpoints
  • Cell Cycle Proteins
  • DNA Breaks, Double-Stranded
  • Endopeptidases
  • Green Fluorescent Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Protein-Serine-Threonine Kinases
  • Saccharomyces cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Saccharomycetales
  • Securin
  • Separase
  • Sirolimus