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

• Published in: Scientific reports Vol. 10; no. 1; p. 13942
• Main Authors: Sweeney, Melanie A., Iakova, Polina, Maneix, Laure, Shih, Fu-Yuan, Cho, Hannah E., Sahin, Ergun, Catic, Andre
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.08.2020; Nature Publishing Group
• Subjects: 631/208/199; 631/80/474/2073; Biodegradation; c-Myc protein; Cell Nucleus - metabolism; Chromatin; Chromatin - metabolism; Cullin; Cullin Proteins - genetics; Cullin Proteins - metabolism; Deoxyribonucleic acid; DNA; DNA-Binding Proteins; Gene regulation; Genes; Genes, myc; HeLa Cells; Humanities and Social Sciences; Humans; Mitochondria; Mitochondrial DNA; multidisciplinary; Myc protein; Nucleotide sequence; Post-translation; Proteasomes; Protein Binding; Protein Processing, Post-Translational; Proteins; Proteolysis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Science; Science (multidisciplinary); Splicing; Transcription factors; Transcription Factors - metabolism; Transcription, Genetic; Ubiquitin; Ubiquitin - metabolism; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-70610-0

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.