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

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 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.

The Role of the COP9 Signalosome and Neddylation in DNA Damage Signaling and Repair

“…This is accompanied by increased γH2AX, and activation of cell cycle checkpoint proteins. In addition, both ATM and ATR mediated effects are increased in response to CSN5 knockdown [ 14 , 148 ]. Since CSN5 harbours the deneddylase enzyme activity of the CSN complex, this data implies a possible role for deneddylation in DNA DSB repair.…”

“…In eukaryotes that have simpler CSN complexes, such as yeast, several subunit deletions are viable [ 8 , 9 , 10 ]. However, null deletions in other organisms are lethal early in development [ 11 , 12 , 13 ], and conditional knockouts result in developmental phenotypes and impaired cellular functional [ 14 ], suggesting an increase in functional complexity as the CSN evolved. The role of the CSN is to deneddylate substrates, particularly cullin-RING E3 ubiquitin ligases (CRLs) in the ubiquitin proteasome pathway [ 15 , 16 ].…”

Role of the COP9 Signalosome in Gastrointestinal Cancers

“…These cells underwent massive, uncontrolled DNA rereplication, indicating that the CSN might be a key repressor of DNA re-replication in the course of normal cell proliferation. Together, this study revealed that hepatic Csn5, in collaboration with Myc, affects the cell cycle and DNA replication [76].…”

“…Besides, a CSN5 knockdown in HuH7 HCC cells resulted in a significant downregulation of 83 genes that were also significantly elevated in early HCC in comparison to dysplastic nodules (HCC precursors) or cirrhotic (regenerative) nodules [74]. Supporting the hypothesis that CSN5 overexpression could drive MYC-dependent transactivation and thereby HCC progress, Panattoni et al recently uncovered the relationship of Csn5 and Myc in the regenerating mouse liver [76]. Here, liver-specific Csn5 deletion leads to replicative stress resulting in cell cycle arrest, polyploidy and apoptosis of hepatocytes.…”

Cuproptosis related genes associated with Jab1 shapes tumor microenvironment and pharmacological profile in nasopharyngeal carcinoma

“…For example, Jab1 is required for both Toll-like receptor and reactive oxygen species-mediated deneddylation of Cul3, which is essential for Cul3/Keap1-mediated degradation of NFE2L2 (17). Introducing the Jab1 deletion into the CDKN2A null background led to a complete rescue of liver structure and function and to a complete reversal of the DNA repairassociated genetic program resulting from Jab1 inactivation (18). The interaction between NLRP3 and Jab1 was also observed in THP-1 cells (19).…”