During chaperone-mediated autophagy (CMA), substrates destined for degradation are recognized by heat shock cognate 70 (HSC70), which transfers them to the receptor lysosome-associated membrane protein 2A (LAMP2A) for translocation into the lysosome. Park et al. identify checkpoint kinase 1 (CHK1) as a target of CMA following genotoxic stress. LAMP2A-null cells had higher levels of nuclear CHK1 and DNA damage in response to damaging agents; increased levels of CHK1 enabled DNA damage to accumulate by preventing cell cycle progression. In control cells, CHK1 was degraded by CMA, as judged by its association with lysosomes and HSC70, and its increased levels when lysosomal activity was blocked. Inhibiting nuclear export reduced CHK1 degradation following etoposide treatment, suggesting that nuclear CHK1 is degraded by CMA following DNA damage. As preventing CMA, and thus increasing nuclear CHK1 levels, destabilized the DNA repair complex MRN (MRE11–RAD50–NBS1), CMA-mediated CHK1 degradation might protect cells against genotoxic stress.
References
Park, C., Suh, Y. & Cuervo, A. M. Regulated degradation of Chk1 by chaperone-mediated autophagy in response to DNA damage. Nature Commun. 6, 6823 (2015)
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Wrighton, K. Chaperone-mediated autophagy degrades CHK1. Nat Rev Mol Cell Biol 16, 328 (2015). https://doi.org/10.1038/nrm4003
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DOI: https://doi.org/10.1038/nrm4003