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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 7; pp. E1158 - E1167
• Main Authors: Eapen, Vinay V., Waterman, David P., Bernard, Amélie, Schiffmann, Nathan, Sayas, Enrich, Kamber, Roarke, Lemos, Brenda, Memisoglu, Gonen, Ang, Jessie, Mazella, Allison, Chuartzman, Silvia G., Loewith, Robbie J., Schuldiner, Maya, Denic, Vladimir, Klionsky, Daniel J., Haber, James E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.02.2017
• Series: PNAS Plus
• Subjects: Autophagy; Autophagy - genetics; Autophagy-Related Proteins - genetics; Autophagy-Related Proteins - metabolism; Biological Sciences; 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; PNAS Plus; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - genetics; Saccharomyces cerevisiae Proteins - metabolism; Signal Transduction - genetics; Transcription factors; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; Yeast; budding yeast; autophagy; ATM kinase; DNA damage; ATR kinase
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1614364114

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.