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Project presentations on the website
Every project supported by Gebert Rüf Stiftung is made accessible with a web presentation that informs about the core data of the project. With this public presentation, the foundation publishes the funding results achieved and contributes to the communication of science to society.
Towards Small Molecule Intervention in Cockayne Syndrome – Rare Diseases 2014
Editorial
Für den Inhalt der Angaben zeichnet die Projektleitung verantwortlich.
Cooperation
This project is one of the five winners of the call 2014 «Rare Diseases - New Approaches». Project partners: Friedrich Miescher Instittute for Biomedical Research (FMI); Novartis Institute of BioMedical Research (NIBR); University of Basel
Project data
- Project no: GRS-057/14
- Amount of funding: CHF 480'000
- Approved: 06.11.2014
- Duration: 07.2015 - 01.2020
- Area of activity: Rare Diseases, 2009 - 2014
Project management
- Dr. Nicolas Thomä, Senior Group Leader Structural Biology
- Friedrich Miescher Institute for Biomedical Research
- Maulbeerstrasse 66
- 4056 Basel (Schweiz)
- nicolas.thoma@fmi.ch
Project description
Mechanisms that preserve genomic integrity are central pillars of human health. This proposal focuses on potential treatments for Cockayne Syndrome (CS), a rare congenital DNA repair defect, where loss of genome maintenance systems gives rise to growth defects, neurological abnormalities and accelerated aging. Cells from Cockayne syndrome patients are unable to effectively repair UV damaged DNA bases, or DNA adducts, in the actively transcribed DNA strand. They also appear compromised in their transcriptional programs and affected children are slowed in their development, and in addition rapidly develop signs of aging such as cataracts, hair loss, calcification etc. all otherwise associated with normal aging. Mutations in two proteins (CSA & CSB) result in the disease. CSA functions as substrate receptor for the DDB1-CUL4-RBX1 ubiquitin E3 ligase, a protein destruction machine, presumed to mark CSB for degradation by the proteosome. No therapy is currently available.
What is special about the project?
The point mutations observed in Cockayne syndrome render the CSA protein complexes non-functional. We will attempt to develop small molecules that compensate for these mutations and hence repair the gene defect restoring the ubiquitin ligase function.
Status/Results
Our previous work demonstrated that small molecular weight compounds can modulate and re-direct ubiquitin ligase function (Fischer et al., Nature 2014; Petzold et al, 2016). We have also provided structures of the CSA ubiquitin ligase, establishing a first molecular rationale for mutations that result in Cockayne syndrome (Fischer, Scrima et al., Cell 2011). We will try to bring these two areas of expertise together in search for a potential therapeutic intervention. Such compounds are beginning to emerge (Lai & Crews, 2016) and represent a new class of therapeutics that can achieve what conventional pharmacological inhibitors were unable to do.
Publications
The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation. Fischer ES, Scrima A, Böhm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thomä NH.
Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide; Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM, Tichkule RB, Schebesta M, Forrester WC, Schirle M, Hassiepen U, Ottl J, Hild M, Beckwith RE, Harper JW, Jenkins JL, Thomä NH; Cell. 2011 Nov 23;147(5):1024-39. doi: 10.1016/j.cell.2011.10.035;
Structural basis of lenalidomide-induced CK1 degradation by the CRL4(CRBN) ubiquitin ligase. Petzold G, Fischer ES, Thomä NH.
Nature. 2016 Apr 7;532(7597):127-30. doi: 10.1038/nature16979;
Induced protein degradation: an emerging drug discovery paradigm. Lai AC, Crews CM. Nat Rev Drug Discov. 2016 Nov 25. doi: 10.1038/nrd.2016.211.
Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide; Fischer ES, Böhm K, Lydeard JR, Yang H, Stadler MB, Cavadini S, Nagel J, Serluca F, Acker V, Lingaraju GM, Tichkule RB, Schebesta M, Forrester WC, Schirle M, Hassiepen U, Ottl J, Hild M, Beckwith RE, Harper JW, Jenkins JL, Thomä NH; Cell. 2011 Nov 23;147(5):1024-39. doi: 10.1016/j.cell.2011.10.035;
Structural basis of lenalidomide-induced CK1 degradation by the CRL4(CRBN) ubiquitin ligase. Petzold G, Fischer ES, Thomä NH.
Nature. 2016 Apr 7;532(7597):127-30. doi: 10.1038/nature16979;
Induced protein degradation: an emerging drug discovery paradigm. Lai AC, Crews CM. Nat Rev Drug Discov. 2016 Nov 25. doi: 10.1038/nrd.2016.211.
Media
Protein superglue! What this means for drug discovery?, TEDx Talk, 17.7.2019
Körpereigene Hautkrebs Prophylaxe entdeckt, sprechzimmer.ch, 30.11.2011
Basler Forscher entschlüsseln körpereigene Hautkrebs-Prophylaxe. südostschweiz.ch, 30.11.2011
Körpereigene Hautkrebs Prophylaxe entdeckt, sprechzimmer.ch, 30.11.2011
Basler Forscher entschlüsseln körpereigene Hautkrebs-Prophylaxe. südostschweiz.ch, 30.11.2011
Links
Persons involved in the project
Dr. Nicolas Thomä, Friedrich Miescher Instittute for Biomedical Research (FMI)
Last update to this project presentation 27.01.2020