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

Martina Panattoni, Laura Maiorino, Anna Lukacs, Lorena Zentilin, Davide Mazza, Francesca Sanvito, Giovanni Sitia, Luca G. Guidotti, Ruggero Pardi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2331-2343
Number of pages13
JournalHepatology
Volume59
Issue number6
DOIs
Publication statusPublished - 2014

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Liver
Ligases
Cell Cycle Checkpoints
DNA Replication
Proto-Oncogene Proteins
Hepatocytes
Cell Cycle
Cullin Proteins
G2 Phase Cell Cycle Checkpoints
Apoptosis
Replication Origin
Polyploidy
Oncogene Proteins
Licensure
Ubiquitin
Hepatocellular Carcinoma
Catalytic Domain
Cell Death
COP9 signalosome complex

ASJC Scopus subject areas

  • Hepatology

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The COP9 signalosome is a repressor of replicative stress responses and polyploidization in the regenerating liver. / Panattoni, Martina; Maiorino, Laura; Lukacs, Anna; Zentilin, Lorena; Mazza, Davide; Sanvito, Francesca; Sitia, Giovanni; Guidotti, Luca G.; Pardi, Ruggero.

In: Hepatology, Vol. 59, No. 6, 2014, p. 2331-2343.

Research output: Contribution to journalArticle

Panattoni, Martina ; Maiorino, Laura ; Lukacs, Anna ; Zentilin, Lorena ; Mazza, Davide ; Sanvito, Francesca ; Sitia, Giovanni ; Guidotti, Luca G. ; Pardi, Ruggero. / The COP9 signalosome is a repressor of replicative stress responses and polyploidization in the regenerating liver. In: Hepatology. 2014 ; Vol. 59, No. 6. pp. 2331-2343.
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