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.
Highlights
Transcription is regulated through a dynamic interplay of DNA-associated proteins, and the composition of gene-regulatory complexes is subject to continuous adjustments
Notwithstanding the fact that CUL1 and its most divergent paralog CUL7 feature a combined 53.4% amino acid sequence similarity and identity (Fig. 1C), both are essential for viability and cannot be rescued by the presence of any other cullin[25,26,27]
We here identify a novel role of the ubiquitin ligase CUL1 as a transcriptional repressor
Summary
Transcription is regulated through a dynamic interplay of DNA-associated proteins, and the composition of gene-regulatory complexes is subject to continuous adjustments. 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 p roteins[5,6]. The ubiquitin–proteasome system allows for specific ubiquitination of proteins through E3 ubiquitin ligases, of which there are around 600 subunits encoded in the human genome These subunits often assemble into larger complexes with multiple variable subunits, increasing the actual number of functional E3 complexes multifold through combinatorial diversity. Cullin ubiquitin ligases impact a variety of vital cellular functions, such as cell cycle progression, signaling, and DNA repair Their specific role in transcriptional regulation is less well u nderstood[13,15]
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