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
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Autophagy / genetics*
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Autophagy-Related Proteins / genetics
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Autophagy-Related Proteins / metabolism
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Checkpoint Kinase 2 / genetics
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Checkpoint Kinase 2 / metabolism
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DNA Breaks, Double-Stranded*
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DNA Damage*
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DNA Repair
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DNA, Fungal / genetics
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DNA, Fungal / metabolism
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Saccharomyces cerevisiae / genetics*
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Saccharomyces cerevisiae / metabolism
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism
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Signal Transduction / genetics*
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Vesicular Transport Proteins / genetics
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Vesicular Transport Proteins / metabolism
Substances
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Atg11 protein, S cerevisiae
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Autophagy-Related Proteins
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Cell Cycle Proteins
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DNA, Fungal
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Intracellular Signaling Peptides and Proteins
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Saccharomyces cerevisiae Proteins
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Vesicular Transport Proteins
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Checkpoint Kinase 2
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MEC1 protein, S cerevisiae
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Protein Serine-Threonine Kinases
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RAD53 protein, S cerevisiae