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The COP9 signalosome is a repressor of replicative stress responses and polyploidization in the regenerating liver
Author(s) -
Panattoni Martina,
Maiorino Laura,
Lukacs Anna,
Zentilin Lorena,
Mazza Davide,
Sanvito Francesca,
Sitia Giovanni,
Guidotti Luca G.,
Pardi Ruggero
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27028
Subject(s) - cop9 signalosome , biology , cullin , cell cycle , microbiology and biotechnology , dna damage , ubiquitin , dna replication , apoptosis , cancer research , genetics , ubiquitin ligase , dna , gene , biochemistry , protease , peptide hydrolases , enzyme
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. 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. (H epatology 2014;59:2331–2343)