1. Xeroderma Pigmentosum (XPF) Cara Mitchell

2. 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

3. Affected Individual  http://www.inrp.fr/Acces/biotic/gpe/dossiers/xeroderma/html/phenomacr.htm

4. 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

5. What is NER?  Nucleotide Excision Repair  Mechanism of DNA repair  Used in repairing UV damage http://murray.francis.com/repair/3-UVcancer.htm

6. 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

7. Complementation Groups  7 main proteins involved in NER  Mutations are generally recessive  Mutations in XPA-G are complementary  Different phenotypes possible

8. XP-F  Milder phenotype  Later onset of cancers  Usually no neurological damage  Lessened photosensitivity

9. 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

10. 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

11. Back to the Big Picture  XPF: endonuclease activity in NER  NER repairs UV damage to DNA  Dysfunctional NER Buildup of mutations Cancer

12. Protein Therapy  Now in clinical trials  Introduces desired protein into cells  Uses viral proteins  Goes on via skin lotion!  Does not help neurological problems

13. 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://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.rarediseases.org/search/rdbdetail_ab stract.html?disname=Xeroderma%20Pigmentosu m  http://www.xps.org/ http://www.xps.org/  http://www.bio.unc.edu/courses/Biology99/exam ples/Kramer.ppt#1 http://www.bio.unc.edu/courses/Biology99/exam ples/Kramer.ppt#1  http://www.cse.ucsc.edu/research/compbio/DNA- repair/euk-nucleotide-excision.html http://www.cse.ucsc.edu/research/compbio/DNA- repair/euk-nucleotide-excision.html  http://mcb.asm.org/cgi/content/full/24/3/1200 http://mcb.asm.org/cgi/content/full/24/3/1200

14. Thanks for Listening! Questions?