The COP9 signalosome is a repressor of replicative stress responses and polyploidization in the regenerating liver.
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 ill-defined 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.


CONCLUSIONS
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.
Leukocyte Biology Unit, Ospedale San Raffaele Scientific Institute, Milano, Italy.
Martina
M
Panattoni
Laura
L
Maiorino
Anna
A
Lukacs
Lorena
L
Zentilin
Davide
D
Mazza
Francesca
F
Sanvito
Giovanni
G
Sitia
Luca G
LG
Guidotti
Ruggero
R
Pardi
D000818:Animals; D000075686:COP9 Signalosome Complex; D004261:DNA Replication; D005260:Female; D016259:Genes, myc; D019942:Genes, p16; D022781:Hepatocytes / Q000502:physiology*; D006706:Homeostasis; D008099:Liver / Q000502:physiology / Q000503:physiopathology; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000502:physiology*; D010447:Peptide Hydrolases / Q000502:physiology*; D011123:Polyploidy
D046912:Multiprotein Complexes; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex