The ubiquitin-proteasome system is the principal cellular mechanism for selective protein removal. Transcription factors and chromatin modifiers are short-lived proteins and associated with defined DNA regions. The activity as well as the elimination of these proteins occur in a site-specific context. We study which elements of the ubiquitin-proteasome system are involved in spatially restricted degradation in the nucleus and how this impacts gene activity.

Ubiquitin ligases in transcriptional control

Cullin-RING ligases represent the largest family of ubiquitin ligases. In an effort to define their role in transcription regulation, we mapped the subcellular locations and DNA affinities of the seven core cullin proteins. We identified that CUL1 associates with active promoter sequences and co-distributes with the transcription factor c-MYC. CUL1 represses specific metabolic genes that regulate mitochondrial activity.

Figure 1: Intracellular distribution of cullin proteins in human cells.
Figure 2: ChIP-sequencing peaks of individual cullins show strong chromatin association of CUL1.

The proteasome as chromatin regulator

The proteasome is responsible for the elimination of most transcription factors. We discovered that inhibition of the proteasome dramatically changes the epigenetic landscape and represses genes involved in cell proliferation. One of our main projects is to identify the mechanism behind these findings and to investigate how this pathway contributes to the clinical effect of proteasome inhibitors in cancer treatment.

c-MYC degradation shapes transcriptional activity

The proto-oncogene MYC is a vital driver of regeneration and growth. As a short-lived transcription factor, MYC is continuously targeted for degradation by the ubiquitin-proteasome system. Ongoing research in our laboratory addresses how this pathway targets MYC at specific genomic locations and how the half-life of MYC varies across the many promoters it binds to.