Project

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Structural studies of the molecular defence against skin cancer

English title Structural studies of the molecular defence against skin cancer
Applicant Thomä Nicolas
Number 120205
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Structural Research
Start/End 01.12.2008 - 30.11.2011
Approved amount 277'425.00
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All Disciplines (2)

Discipline
Structural Research
Genetics

Keywords (7)

nucleotide excision repair; skin cancer; ubiquitin transferases; DNA repair interactions; structural biology; chromatin; ubiquitination

Lay Summary (English)

Lead
Lay summary
The nucleotide excision repair pathway recognizes and repairs UV-induced DNA base lesions, including the highly mutagenic cyclobutane pyrimidine dimers (CPD). If these types of DNA damage are left unrepaired, they give rise to mutations, which in turn result in skin cancer formation. Indeed, a large number of mutations found in sun exposed malignant melanomas are due to the failure to accurately repair these photodimers. We study the UV-DNA damage binding complex (UV-DDB). The UV-DDB complex contains two principle protein subunits DDB1 (p127) and DDB2 (p48). Mutations in DDB2 give rise to XP complementation group E, a human UV-sensitivity syndrome characterized by a heightened propensity for skin tumor formation. Several lines of evidence indicate that UV-DDB complex is the NER factor specialized for the detection of UV-induced lesions in chromatin. In vitro, UV-DDB binds to pyrimidine dimers including isomers of CPD and 6-4PP with the highest reported affinity and specificity of all GG-NER proteins. In vivo, DDB2 localizes to the lesion ahead of other nucleotide excision repair factors such as XPC and XPA.In the grant proposal, we intend to study the mechanism by which damaged bases such as cyclobutane pyrimidine dimers and 6-4 pyrimidine pyrimidone photoproducts are recognized with high affinity and specificity. Using X-ray crystallography, we intend to visualize the DDB1-DDB2 protein complex bound to oligonucleotides containing photodimers. This work will allow us to better underdstand how the DDB1-DDB2 complex is able to find UV-induced DNA damage within a large genome.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
The Molecular Basis of CRL4(DDB2/CSA) Ubiquitin Ligase Architecture, Targeting, and Activation
Fischer ES, Scrima A, Bohm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thoma NH (2011), The Molecular Basis of CRL4(DDB2/CSA) Ubiquitin Ligase Architecture, Targeting, and Activation, in CELL, 147(5), 1024-1039.
Detecting UV-lesions in the genome: The modular CRL4 ubiquitin ligase does it best!
Scrima A, Fischer ES, Lingaraju GM, Bohm K, Cavadini S, Thoma NH (2011), Detecting UV-lesions in the genome: The modular CRL4 ubiquitin ligase does it best!, in FEBS LETTERS, 585(18), 2818-2825.
Determinants and dynamics of genome accessibility
Bell O, Tiwari VK, Thoma NH, Schubeler D (2011), Determinants and dynamics of genome accessibility, in NATURE REVIEWS GENETICS, 12(8), 554-564.
Structural Basis of UV DNA-Damage Recognition by the DDB1-DDB2 Complex
Scrima A, Konickova R, Czyzewski BK, Kawasaki Y, Jeffrey PD, Groisman R, Nakatani Y, Iwai S, Pavletich NP, Thoma NH (2008), Structural Basis of UV DNA-Damage Recognition by the DDB1-DDB2 Complex, in CELL, 135(7), 1213-1223.
Structure of rab escort protein-1 in complex with Rab geranylgeranyltransferase
Pylypenko O, Rak A, Reents R, Niculae A, Sidorovitch V, Vioaca MD, Bessolitsyna E, Thoma NH, Waldmann H, Schlichting I, Goody RS, Alexandrov K (2003), Structure of rab escort protein-1 in complex with Rab geranylgeranyltransferase, in MOLECULAR CELL, 11(2), 483-494.

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