Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 7, Pages E1158-E1167Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1614364114
Keywords
DNA damage; autophagy; ATM kinase; ATR kinase; budding yeast
Categories
Funding
- Howard Hughes Medical Institute international predoctoral fellowship
- National Institutes of Health (NIH) Genetics Training Grant [TM32 GM007122]
- NIH [GM61766, GM20056, GM053396]
- Bronfman Brandeis-Israel collaborative research grant
- Harvard University
- BSF [2013101]
- Canton of Geneva a
- Singal X of the Swiss National Science Foundation's Systems X program
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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 similar to 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.
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