PMID- 25880015
OWN - NLM
STAT- MEDLINE
DCOM- 20160405
LR  - 20201209
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 6
DP  - 2015 Apr 16
TI  - Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA 
      damage.
PG  - 6823
LID - 10.1038/ncomms7823 [doi]
AB  - 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.
FAU - Park, Caroline
AU  - Park C
AD  - 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.
FAU - Suh, Yousin
AU  - Suh Y
AD  - 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.
FAU - Cuervo, Ana Maria
AU  - Cuervo AM
AUID- ORCID: 000000020771700X
AD  - 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.
LA  - eng
GR  - R01 AG021904/AG/NIA NIH HHS/United States
GR  - P30 DK041296/DK/NIDDK NIH HHS/United States
GR  - AG031782/AG/NIA NIH HHS/United States
GR  - AG17242/AG/NIA NIH HHS/United States
GR  - R37 AG021904/AG/NIA NIH HHS/United States
GR  - R01 GM104459/GM/NIGMS NIH HHS/United States
GR  - GM104459/GM/NIGMS NIH HHS/United States
GR  - AG038072/AG/NIA NIH HHS/United States
GR  - P30 AG038072/AG/NIA NIH HHS/United States
GR  - P01 AG017242/AG/NIA NIH HHS/United States
GR  - T32GM007288/GM/NIGMS NIH HHS/United States
GR  - R01 DK098408/DK/NIDDK NIH HHS/United States
GR  - T32 GM007288/GM/NIGMS NIH HHS/United States
GR  - R01 AG024391/AG/NIA NIH HHS/United States
GR  - P30 CA013330/CA/NCI NIH HHS/United States
GR  - P01 AG031782/AG/NIA NIH HHS/United States
GR  - AG21904/AG/NIA NIH HHS/United States
GR  - DK098408/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150416
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Mre11 protein, rat)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (Checkpoint Kinase 1)
RN  - EC 2.7.11.1 (Chek1 protein, mouse)
RN  - EC 2.7.11.1 (Chek1 protein, rat)
RN  - EC 3.1.- (MRE11 Homologue Protein)
RN  - EC 3.6.- (Acid Anhydride Hydrolases)
RN  - EC 3.6.- (Rad50 protein, mouse)
RN  - EC 6.5.1.- (DNA Repair Enzymes)
SB  - IM
MH  - ATP-Binding Cassette Transporters/metabolism
MH  - Acid Anhydride Hydrolases
MH  - Animals
MH  - Autophagy/*genetics
MH  - Cell Cycle/genetics
MH  - Cell Cycle Proteins
MH  - Cell Survival/genetics
MH  - Checkpoint Kinase 1
MH  - Comet Assay
MH  - DNA Damage/*genetics
MH  - DNA Repair Enzymes
MH  - DNA-Binding Proteins
MH  - Genomic Instability
MH  - Lysosomes/*metabolism
MH  - MRE11 Homologue Protein
MH  - Male
MH  - Mice
MH  - Microscopy, Fluorescence
MH  - NIH 3T3 Cells
MH  - Nuclear Proteins
MH  - Phosphorylation
MH  - Protein Kinases/*genetics/metabolism
MH  - RNA, Messenger/*metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Up-Regulation
PMC - PMC4400843
MID - NIHMS669416
COIS- Competing financial interest The authors declare that they have no competing 
      interests.
EDAT- 2015/04/17 06:00
MHDA- 2016/04/06 06:00
PMCR- 2015/10/16
CRDT- 2015/04/17 06:00
PHST- 2014/08/21 00:00 [received]
PHST- 2015/03/03 00:00 [accepted]
PHST- 2015/04/17 06:00 [entrez]
PHST- 2015/04/17 06:00 [pubmed]
PHST- 2016/04/06 06:00 [medline]
PHST- 2015/10/16 00:00 [pmc-release]
AID - ncomms7823 [pii]
AID - 10.1038/ncomms7823 [doi]
PST - epublish
SO  - Nat Commun. 2015 Apr 16;6:6823. doi: 10.1038/ncomms7823.