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Xeroderma Pigmentosum (XPF) Cara Mitchell Characteristics of XP Extreme photosensitivity Early onset of skin cancers Blistering of skin from sun exposure Redness and inflammation of skin Discoloration, scarring, freckling Some neurological damage Affected Individual http://www.inrp.fr/Acces/biotic/gpe/dossiers/xeroderma/html/phenomacr.htm Cause of XP Mutation in one of the proteins involved in NER Inability to repair UV damaged DNA Buildup of mutations in skin cells Increased incidence of skin cancers What is NER? Nucleotide Excision Repair Mechanism of DNA repair Used in repairing UV damage http://murray.francis.com/repair/3-UVcancer.htm NER in the cell Damage Recognition Binding of protein complex 5’ 3’ Incision of DNA Oligonucleotide excision DNA repair synthesis http://egp.gs.washington.edu/ner.html Complementation Groups 7 main proteins involved in NER Mutations are generally recessive Mutations in XPA-G are complementary Different phenotypes possible XP-F Milder phenotype Later onset of cancers Usually no neurological damage Lessened photosensitivity XPF Protein Functions with ERCC1 protein XPF-ERCC1: endonuclease activity Incises DNA 5’ to the damage Mutations mostly in C-terminal half This half associates w/ ERCC1 and has nuclease function Mouse Knockouts (XPF Deficient) Severely defective postnatal growth Death at ~3 weeks Abnormal cells (esp. in liver) Embryonic fibroblasts hypersensitive to UV and MMC Liver Cells http://mcb.asm.org/cgi/content/full/24/3/1200 Back to the Big Picture XPF: endonuclease activity in NER NER repairs UV damage to DNA Dysfunctional NER Buildup of mutations Cancer Protein Therapy Now in clinical trials Introduces desired protein into cells Uses viral proteins Goes on via skin lotion! Does not help neurological problems Sources Friedberg, Errol C. “How nucleotide excision repair protects against cancer”, Nature. Oct. 2001 vol. 1. Macmillan Magazines Ltd. http://hmg.oupjournals.org/cgi/content/full/7/6/9 69 http://www.rarediseases.org/search/rdbdetail_ab stract.html?disname=Xeroderma%20Pigmentosu m http://www.xps.org/ http://www.bio.unc.edu/courses/Biology99/exam ples/Kramer.ppt#1 http://www.cse.ucsc.edu/research/compbio/DNArepair/euk-nucleotide-excision.html http://mcb.asm.org/cgi/content/full/24/3/1200 Thanks for Listening! Questions?
