Publication Date
8-18-2020
Journal
Scientific Reports
DOI
10.1038/s41598-020-70610-0
PMID
32811853
PMCID
PMC7435197
PubMedCentral® Posted Date
8-18-2020
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Cell Nucleus, Chromatin, Cullin Proteins, DNA-Binding Proteins, Genes, myc, HeLa Cells, Humans, Protein Binding, Protein Processing, Post-Translational, Proteolysis, Proto-Oncogene Proteins c-myc, Transcription Factors, Transcription, Genetic, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination
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 site- and 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 DNA-bound 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.
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Biology Commons, Genetic Phenomena Commons, Genetic Processes Commons, Genetic Structures Commons, Medical Genetics Commons, Medical Specialties Commons
