Group Beli

Ubiquitin-proteasome system in the regulation of transcriptional elongation during UV stress response

Group Leader

Petra Beli

Petra Beli is adjunct director at the Institute of Molecular Biology (IMB) and a full professor at Johannes Gutenberg-Universität Mainz. Her groups develops and employs quantitative MS-based proteomics approaches to analyze ubiquitin signaling and DNA damage response.

Projects within consortium

Ultraviolet light (UV) triggers the formation of bulky adducts in the genome that interfere with transcription. As consequence, cellular response to UV stress involves multifaceted mechanisms that regulate RNAPII-dependent transcriptional initiation and elongation. In this project, we seek to obtain a better understanding of targeted protein degradation events that regulate transcriptional elongation during UV stress response and thereby protect human cells from genomic instability arising from exposure to UV light.

Ultraviolet light (UV) triggers the formation of bulky adducts in the genome that interfere with transcription. Failure to repair these DNA lesions due to somatic or inherited mutations in nucleotide excision repair (NER) factors leads to accumulation of mutations and human syndromes including cancer and premature aging. We have recently shown that UV light promotes the release of the paused RNA polymerase II (RNAPII) from promoter-proximal sites through a mechanism that involves the dissociation of the negative elongation factor (NELF) complex from chromatin. This rapid release of paused RNAPII promotes the repair of UV-induced DNA lesions and hence protects the cells from genomic instability.

In this project, we will combine mass spectrometry (MS)-based proteomics, genomics and biochemical approaches to define the interplay between the ubiquitin proteasome system (UPS) and NELF-dependent regulation of transcriptional elongation during UV stress response. In particular, we will investigate the UPS-dependent mechanisms that regulate NELF complex turnover on chromatin in response to UV.  The results of this project will deliver insights into the role of UPS and targeted protein degradation in the regulation of chromatin-associated protein complexes and transcription during stress response

Regulation of the NELF complex in response to UV stress. NELF complex is phosphorylated by p38-MK2 in response to UV stress. NELF phosphorylation recruits 14-3-3 and results in NELF complex dissociation from chromatin that is accompanied by RNAPII elongation

Project members

Targeted Protein Degradation related publications by Group Beli

  • 2019 The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation Genome Biol. Hildebrandt A, Brüggemann M, Rücklé C, Boerner S, Heidelberger JB, Busch A, Hänel H, Voigt A, Möckel MM, Ebersberger S, Scholz A, Dold A, Schmid T, Ebersberger I, Roignant JY, Zarnack K, König J, Beli P Go to publication →
  • 2018 p38-MK2 signaling axis regulates RNA metabolism after UV-light-induced DNA damage Nat. Commun. Borisova ME, Voigt A, Tollenaere MAX, Sahu SK, Juretschke T, Kreim N, Mailand N, Choudhary C, Bekker-Jensen S, Akutsu M, Wagner SA, Beli P Go to publication →
  • 2018 Proteomic profiling of VCP substrates links VCP to K6-linked ubiquitylation and c-Myc function EMBO Rep. Heidelberger JB, Voigt A, Borisova ME, Petrosino G, Ruf S, Wagner SA, Beli P Go to publication →