title: Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage.
abstract: Chaperone-mediated autophagy (CMA) is activated in response to cellular stressors to prevent cellular proteotoxicity through selective degradation of altered proteins in lysosomes. Reduced CMA activity contributes to the decrease in proteome quality in disease and ageing. Here, we report that CMA is also upregulated in response to genotoxic insults and that declined CMA functionality leads to reduced cell survival and genomic instability. This role of CMA in genome quality control is exerted through regulated degradation of activated checkpoint kinase 1 (Chk1) by this pathway after the genotoxic insult. Nuclear accumulation of Chk1 in CMA-deficient cells compromises cell cycle progression and prolongs the time that DNA damage persists in these cells. Furthermore, blockage of CMA leads to hyperphosphorylation and destabilization of the MRN (Mre11-Rad50-Nbs1) complex, which participates in early steps of particular DNA repair pathways. We propose that CMA contributes to maintain genome stability by assuring nuclear proteostasis.
authors.affiliation: 1] Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA [2] Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA [3] Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Park
authors.affiliation: 1] Department of Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA [2] Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.affiliation: 1] Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA [2] Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
authors.forename: Ana Maria
authors.identifier: 000000020771700X
authors.initials: AM
authors.lastname: Cuervo
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D017766:Acid Anhydride Hydrolases; D000818:Animals; D001343:Autophagy / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D002470:Cell Survival / Q000235:genetics; D000071877:Checkpoint Kinase 1; D020552:Comet Assay; D004249:DNA Damage / Q000235:genetics*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D042822:Genomic Instability; D008247:Lysosomes / Q000378:metabolism*; D000076228:MRE11 Homologue Protein; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation
chemical_list: D018528:ATP-Binding Cassette Transporters; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512690:Mre11 protein, rat; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; C000605871:Chek1 protein, rat; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C495198:Rad50 protein, mouse; D045643:DNA Repair Enzymes