Previously published online as a Cell Cycle E-publication:
Aberrant DNA replication induced by deregulated or excessive proliferative stimuli evokes a "replicative stress response" leading to cell cycle restriction and/or apoptosis. This robust fail-safe mechanism is eventually bypassed by transformed cells, due to illdefined epistatic interactions. The COP9 signalosome (CSN) is an evolutionarily conserved regulator of cullin ring ligases (CRLs), the largest family of ubiquitin ligases in metazoans. Conditional inactivation of the CSN in several tissues leads to activation of S-or G2-phase checkpoints resulting in irreversible cell cycle arrest and cell death. Herein we ablated COPS5, the CSNs catalytic subunit, in the liver, to investigate its role in cell cycle reentry by differentiated hepatocytes. Lack of COPS5 in regenerating livers causes substantial replicative stress, which triggers a CDKN2A-dependent genetic program leading to cell cycle arrest, polyploidy, and apoptosis. These outcomes are phenocopied by acute overexpression of c-Myc in COPS5 null hepatocytes of adult mice. Conclusion: We propose that combined control of proto-oncogene product levels and proteins involved in DNA replication origin licensing may explain the deleterious consequences of CSN inactivation in regenerating livers and provide insight into the pathogenic role of the frequently observed overexpression of the CSN in hepatocellular carcinoma. (HEPATOLOGY 2014;59:2331-2343 T he COP9 signalosome (CSN) is an evolutionarily conserved, eight subunit complex (COPS1-COPS8) displaying structural homology to the 26S proteasome lid. The main established function of the CSN is the enzymatic removal of the ubiquitin-like NEDD8 moiety from the cullin component of cullin-ring ubiquitin ligases (CRLs). Functional and genetic evidence has shown that CSNmediated deneddylation of cullins locates to the metalloprotease JAMM/MPN1 motif of the COPS5 subunit, also known as CSN5 or Jab1. Neddylation of cullins facilitates CRL complex formation and its interaction with substrates.
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