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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.
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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/7/6/969 • http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Xeroderma%20Pigmentosum • http://www.xps.org/ • http://www.bio.unc.edu/courses/Biology99/examples/Kramer.ppt#1 • http://www.cse.ucsc.edu/research/compbio/DNA-repair/euk-nucleotide-excision.html • http://mcb.asm.org/cgi/content/full/24/3/1200
Thanks for Listening! Questions?