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Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage.

Park C, Suh Y, Cuervo AM - Nat Commun (2015)

Bottom Line: 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.We propose that CMA contributes to maintain genome stability by assuring nuclear proteostasis.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus

CMA malfunction results in genome instabilityCMA is upregulated in response to different genotoxic insults to assure timely release of cell cycle arrest after DNA repair, through the selective degradation of nuclear pChk1. When CMA activity is compromised, abnormally high levels of pChk1 persist in the nucleus leading to accumulation of DNA damage and to aberrant hyperphosphorylation of several components of the MRN complex and their subsequent destabilization. These and other alterations in nuclear proteostasis consequence of CMA malfunction could be behind the defective DNA maintenance and repair observed under these conditions.
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Figure 10: CMA malfunction results in genome instabilityCMA is upregulated in response to different genotoxic insults to assure timely release of cell cycle arrest after DNA repair, through the selective degradation of nuclear pChk1. When CMA activity is compromised, abnormally high levels of pChk1 persist in the nucleus leading to accumulation of DNA damage and to aberrant hyperphosphorylation of several components of the MRN complex and their subsequent destabilization. These and other alterations in nuclear proteostasis consequence of CMA malfunction could be behind the defective DNA maintenance and repair observed under these conditions.

Mentions: In summary, we have found that regulated degradation of Chk1 by CMA in response to DNA damage is required to ensure cell cycle progression and that failure to efficiently eliminate Chk1 by this pathway leads to persistent cell arrest, accumulation of DNA damage and alterations in nuclear proteostasis, such as the destabilization of the MRN complex identified in this study (Fig. 10).


Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage.

Park C, Suh Y, Cuervo AM - Nat Commun (2015)

CMA malfunction results in genome instabilityCMA is upregulated in response to different genotoxic insults to assure timely release of cell cycle arrest after DNA repair, through the selective degradation of nuclear pChk1. When CMA activity is compromised, abnormally high levels of pChk1 persist in the nucleus leading to accumulation of DNA damage and to aberrant hyperphosphorylation of several components of the MRN complex and their subsequent destabilization. These and other alterations in nuclear proteostasis consequence of CMA malfunction could be behind the defective DNA maintenance and repair observed under these conditions.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400843&req=5

Figure 10: CMA malfunction results in genome instabilityCMA is upregulated in response to different genotoxic insults to assure timely release of cell cycle arrest after DNA repair, through the selective degradation of nuclear pChk1. When CMA activity is compromised, abnormally high levels of pChk1 persist in the nucleus leading to accumulation of DNA damage and to aberrant hyperphosphorylation of several components of the MRN complex and their subsequent destabilization. These and other alterations in nuclear proteostasis consequence of CMA malfunction could be behind the defective DNA maintenance and repair observed under these conditions.
Mentions: In summary, we have found that regulated degradation of Chk1 by CMA in response to DNA damage is required to ensure cell cycle progression and that failure to efficiently eliminate Chk1 by this pathway leads to persistent cell arrest, accumulation of DNA damage and alterations in nuclear proteostasis, such as the destabilization of the MRN complex identified in this study (Fig. 10).

Bottom Line: 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.We propose that CMA contributes to maintain genome stability by assuring nuclear proteostasis.

View Article: PubMed Central - PubMed

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.

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.

No MeSH data available.


Related in: MedlinePlus