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Molecular mechanism underlying Cockayne Syndrome

Applicant Scrima Andrea
Number 132353
Funding scheme Ambizione
Research institution Helmholtz-Zentrum für Infektionsforschung GmbH
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Biochemistry
Start/End 01.10.2010 - 31.12.2012
Approved amount 185'063.00
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Keywords (5)

Cockayne syndrome; nucleotide excision repair; transcription coupled repair; X-ray crystallography; Cul4 ubiquitin ligase

Lay Summary (English)

Lay summary
Ubiquitination is important in degradation processes and regulation of protein functions. The DDB1-CUL4 ubiquitin ligase catalyzes ubiquitination by recruitment of specific adaptor proteins of the DCAF family (DDB1-CUL4 associated factor), which in turn interact with the ubiquitination substrates and mediate ubiquitination specificity. DDB1-CUL4/DCAF complexes play an important role in the onset of Cockayne Syndrome (CS) and Xeroderma Pigmentosum (XP) disease as well as in various other cellular processes. I will use a combination of X-ray crystallography and protein biochemistry to analyze the structure and function of selected DCAF proteins. Studies of the DDB1-CUL4/DCAF system will help to shed light onto the structure and function of DCAF adaptor proteins and will contribute to our general understanding of DDB1-CUL4 mediated ubiquitination processes.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants



Cockayne syndrome is a congenital disease with impaired DNA repair in actively transcribed genes. It is characterized by heightened photosensitivity, developmental abnormalities and signs of premature aging caused by mutations in the Cockayne syndrome complementation group A (CSA) and B (CSB) genes. The gene products CSA and CSB both play a crucial role in the repair of damaged DNA via the transcription-coupled repair mechanism (TCR) that involves stalling of RNA polymerase II upon encountering a DNA lesion. CSB encodes a SWI2/SNF2 ATPase that likely assists the stalled RNA polymerase in overcoming lesions. The detailed role of CSA is so far elusive. Being part of the CSA-DDB1-CUL4-RBX1 E3 ubiquitin ligase complex, CSA may function as substrate adaptor for ubiquitination by the DDB1-CUL4-RBX1 ligase.I aim at solving the X-ray structure of CSA in complex with DDB1 and the DDB1-CUL4-RBX1 ligase. Co-crystallization with modulators of the ligase activity will allow gaining a detailed molecular insight into the assembly and regulation of the CSA-DDB1-CUL4-RBX1 ligase. To gain a further insight into the function of CSA in TCR, I also want to crystallize CSA with its known interaction partners.The studies presented in this application will constitute a major contribution to our understanding of the molecular mechanism underlying Cockayne syndrome.