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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. - PowerPoint PPT Presentation
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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
http://egp.gs.washington.edu/ner.html
Damage Recognition
Binding of protein complex
3’
Incision of DNA
5’
Oligonucleotide excision
DNA repair synthesis
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
http://mcb.asm.org/cgi/content/full/24/3/1200
Liver Cells
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!
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