The Ubiquitin Ligase Cullin-1 Associates With Chromatin and Regulates Transcription of Specific C-MYC Target Genes

Authors

Melanie A Sweeney
Polina Iakova
Laure Maneix
Fu-Yuan Shih
Hannah E Cho
Ergun Sahin
Andre Catic

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.

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