期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：7
页码：E1158-E1167
DOI：10.1073/pnas.1614364114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe DNA damage response (DDR) is a well-orchestrated and tightly regulated process. The DDR pathway does not act in isolation; indeed, evidence of cross-talk between the DDR and numerous signaling pathways affecting cytoskeletal integrity, nutrient sensing, and autophagy has been demonstrated. In this paper, we report that the DDR induces a distinct pathway of autophagy: genotoxin-induced targeted autophagy (GTA). GTA requires the action of the checkpoint kinases Mec1/ATR, Tel1/ATM, and Rad53/CHEK2. Rad53 mediates the transcriptional up-regulation of autophagy genes via negative regulation of the repressor Rph1/KDM4. GTA requires components of the selective autophagy machinery and is distinct from canonical autophagy pathways. A genome-wide screen for GTA modulators identifies genes required for genotoxin-induced autophagy and starvation-induced autophagy. 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.
