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.
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.
Persons involved in the project
Last update to this project presentation 14.08.2019