A pathway of targeted autophagy is induced by DNA damage in budding yeast.
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.
Department of Biology, Brandeis University, Waltham, MA 02454.
Vinay V
VV
Eapen
Department of Biology, Brandeis University, Waltham, MA 02454.
David P
DP
Waterman
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
Amélie
A
Bernard
Department of Molecular Genetics, Weizmann Institute of Sciences, Rehovot, Israel 7610001.
Nathan
N
Schiffmann
Department of Molecular Biology, University of Geneva, CH-1211 Geneva 4, Switzerland.|Institute of Genetics and Genomics in Geneva, University of Geneva, CH-1211 Geneva 4, Switzerland.
Enrich
E
Sayas
Molecular and Cell Biology, Harvard University, Cambridge, MA 02138.
Roarke
R
Kamber
Department of Biology, Brandeis University, Waltham, MA 02454.
Brenda
B
Lemos
Department of Biology, Brandeis University, Waltham, MA 02454.
Gonen
G
Memisoglu
Department of Biology, Brandeis University, Waltham, MA 02454.
Jessie
J
Ang
Department of Biology, Brandeis University, Waltham, MA 02454.
Allison
A
Mazella
Department of Molecular Genetics, Weizmann Institute of Sciences, Rehovot, Israel 7610001.
Silvia G
SG
Chuartzman
Department of Molecular Biology, University of Geneva, CH-1211 Geneva 4, Switzerland.|Institute of Genetics and Genomics in Geneva, University of Geneva, CH-1211 Geneva 4, Switzerland.
Robbie J
RJ
Loewith
Department of Molecular Genetics, Weizmann Institute of Sciences, Rehovot, Israel 7610001.
Maya
M
Schuldiner
Molecular and Cell Biology, Harvard University, Cambridge, MA 02138.
Vladimir
V
Denic
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
Daniel J
DJ
Klionsky
Department of Biology, Brandeis University, Waltham, MA 02454; haber@brandeis.edu.
James E
JE
Haber
D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
C502923:Atg11 protein, S cerevisiae; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins; D004271:DNA, Fungal; D047908:Intracellular Signaling Peptides and Proteins; D029701:Saccharomyces cerevisiae Proteins; D033921:Vesicular Transport Proteins; D064447:Checkpoint Kinase 2; C088937:MEC1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C067022:RAD53 protein, S cerevisiae
ATM kinase; ATR kinase; DNA damage; autophagy; budding yeast