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Chaque projet soutenu par Gebert Rüf Stiftung est présenté sur le site web de la fondation avec en particulier les données de base du projet. Par cette publication, la fondation informe sur les résultats du soutien accordé et contribue à la communication scientifique au sein de la société.


Towards Small Molecule Intervention in Cockayne Syndrome – Rare Diseases 2014


Für den Inhalt der Angaben zeichnet die Projektleitung verantwortlich.


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

Données de projet

  • Numéro du projet: GRS-057/14 
  • Subside accordé: CHF 480'000 
  • Consentement: 06.11.2014 
  • Durée: 07.2015 - 01.2020 
  • Champs d'activité:  Rare Diseases, 2009 - 2014

Direction du projet

Description du projet

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.

Quelles sont les particularités de ce projet?

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.

Etat/résultats intermédiaires

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.


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.

Revue de presse


Personnes participant au projet

Dr. Nicolas Thomä, Friedrich Miescher Instittute for Biomedical Research (FMI)

Dernière mise à jour de cette présentation du projet  27.01.2020