The ubiquitin ligase Cullin-1 associates with chromatin and regulates transcription of specific c-MYC target genes

Abstract

Transcription is regulated through a dynamic interplay of DNA-associated proteins, and the composition of gene-regulatory complexes is subject to continuous adjustments. Protein alterations include post-translational modifications and elimination of individual polypeptides. Spatially and temporally controlled protein removal is, therefore, essential for gene regulation and accounts for the short half-life of many transcription factors. The ubiquitin-proteasome system is responsible for siteand target-specific ubiquitination and protein degradation. Specificity of ubiquitination is conferred by ubiquitin ligases. Cullin-RING complexes, the largest family of ligases, require multi-unit assembly around one of seven cullin proteins. To investigate the direct role of cullins in ubiquitination of DNAbound proteins and in gene regulation, we analyzed their subcellular locations and DNA-affinities. We found CUL4A and CUL7 to be largely excluded from the nucleus, whereas CUL4B was primarily nuclear. CUL1,2,3, and 5 showed mixed cytosolic and nuclear expression. When analyzing chromatin affinity of individual cullins, we discovered that CUL1 preferentially associated with active promoter sequences and co-localized with 23% of all DNA-associated protein degradation sites. CUL1 co-distributed with c-MYC and specifically repressed nuclear-encoded mitochondrial and splicing-associated genes. These studies underscore the relevance of spatial control in chromatin-associated protein ubiquitination and define a novel role for CUL1 in gene repression. Mammalian gene expression follows oscillatory patterns, caused by alternating binding of transcriptional activators and repressors to specific DNA elements 1. The exchange of regulators during such cycles is partially accomplished through protein removal and subsequent degradation by the ubiquitin-proteasome system 2. Therefore, it is not surprising that transcription factors and their co-regulators are among the most short-lived proteins 3. However, the specific factors that trigger the removal of chromatin-associated proteins, and the genomic locations of degradation remain ill-defined 4. The ubiquitin-proteasome system is a multi-enzyme cascade that triggers the covalent attachment of ubiquitin polypeptides to target proteins. Ubiquitination can impact protein function and trafficking, or mark proteins for proteasomal digestion. The ubiquitin-proteasome system is responsible for the removal of most nuclear and cytosolic proteins. This pathway regulates transcription directly through epigenetic ubiquitination and through poly-ubiquitination that can lead to the removal of DNA-associated proteins 5,6. Furthermore, earlier work by our group and others indicates that the turnover of transcriptional regulators is site-selective and specific to some of the DNA regions to which these proteins are bound. Nuclear degradation by the ubiquitin-proteasome system is therefore not only target protein-selective, but also displays spatial specificity 7,8 .

The Effect of Neddylation Inhibition on Inflammation-Induced MMP9 Gene Expression in Esophageal Squamous Cell Carcinoma

“…The nuclear UPS was found to regulate the turnover of many different components of transcriptional complexes [54]. Particular attention was paid to the role of cullin 1 (CUL1) and cullin 4B (CUL4B) [55]. On the other hand, it is known that in addition to the inhibitory effects of neddylation, MLN4924 also shows neddylation-independent activities.…”

Comparative Proteomic Analysis of Taenia solium Cysticercus and Adult Stages

“…According to the GO analysis, Cullin protein was also involved in cell cycle progression, signal transduction and transcription, intracellular metabolism, and the corresponding response to stimuli. Yet, surprisingly, this protein has not been studied in parasites, we suggested that it could provide clues for the follow-up research [38][39][40]. Topoisomerase was a critical type of enzyme for overcoming the problem of chromosome topology that arose during DNA replication, transcription, recombination, and mitosis.…”

Orientia tsutsugamushi Nucleomodulin Ank13 Exploits the RaDAR Nuclear Import Pathway To Modulate Host Cell Transcription

“…The ubiquitin-proteasome system regulates transcription via polyubiquitination that leads to removal of DNA-associated proteins ( 69 , 70 ). Cul1, an Ank13 interacting partner and SCF component, is abundant in the nucleus and associates with 23% of all DNA-associated protein degradation sites ( 69 ). In addition to commandeering the SCF complex in the cytoplasm, Ank13 does so in the nucleus as its major means of modulating gene expression.…”