Abstract
Chaperone-mediated autophagy (CMA) is activate 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 aging. 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.
Highlights
Chaperone-mediated autophagy (CMA) is activated in response to cellular stressors to prevent cellular proteotoxicity through selective degradation of altered proteins in lysosomes
We have found that CMA participates in the tightly regulated, timely degradation of the cell cycle checkpoint regulator checkpoint kinase 1 (Chk1), thereby allowing disengagement of DNA repair proteins and normal cell cycle progression after DNA repair[17]
CMA participates in the timely degradation of phosphorylated nuclear Chk[1] after DNA repair, and failure to do that leads to persistence of activated pChk[1] in the nucleus and increased genomic instability
Summary
Chaperone-mediated autophagy (CMA) is activated in response to cellular stressors to prevent cellular proteotoxicity through selective degradation of altered proteins in lysosomes. We report that CMA is 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. Selective autophagy contributes to regulate protein function by modulating their intracellular levels and participates in quality control by eliminating damaged proteins and organelles. Prolonged persistence of Chk[1] in the nucleus when CMA is inhibited leads to accumulation of DNA damage and changes in levels of nuclear proteins such as the Mre11–Rad50–Nbs[1] (MRN) complex that participates in the initial processing of double-strand DNA breaks prior to DNA repair by homologous recombination
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