1. Xeroderma Pigmentosum, XPF and Nucleotide Excision Repair By Crystal Stanford

2. Xeroderma Pigmentosum (XP) First discovered in late 1800s by Moritz Kaposi Severe lesions, tumors and skin deformations result from sun exposure Figures from “Living in the Shadows” article

3. Xeroderma Pigmentosum (XP) Autosomal recessive hereditary disease Incidence: 1 in 250,000 in Western world 1 in 40,000 in Japan Disease caused by ineffective DNA repair

4. Xeroderma Pigmentosum (XP) Median age to develop skin cancer is age 8 Incidence of skin cancer is elevated 1000 fold under the age of 20 In 1960s, proved XP was due to defective NER Phenotype can be caused by a mutation in a number of different genes

5. UV damage to DNA UV light causes nucleotide bases to form Thymine- Thymine dimers disrupt DNA synthesis and lead to mutations Figure from Molecular Cell Biology (Lodish)

6. Nucleotide Excision Repair (NER) Responsible for repairing everyday damage to genome Scary fact: “base damage estimated to occur in 25,000 bases per human cell genome per day” ~ that’s a lot of error to catch and correct! NER is a DNA repair mechanism that works by removing the altered base and allowing for resequencing Discovery of pathway

7. NER XPC, XPA recognize base damage (mechanism not understood) Triggers binding of several more proteins, including XPG Binding of ERCC1-XPF endonuclease; NER complex complete Cleavage and removal of damaged oligonucleotide fragment DNA polymerase resynthesizes missing sequence and ligase reseals backbone Figure from Friedberg paper

8. What is XPF? In the NER pathway, XPF forms a heterodimeric endonuclease with ERCC1 The ERCC1-XPF protein is responsible for splicing the 5’ end of the damaged sequence Figure from Friedberg paper

9. Mouse Knockouts ERCC1 knockouts XPF: deficiency vs knockout

10. Treatments & Studies Prevention Gene therapy Dimericine (T4N5 Liposome Lotion) Figure from Dimericine website

11. References Friedberg, Errol C. “How Nucleotide Excision Repair Protects Against Cancer.” Nature Reviews Cancer 1 (2001): 22-30. Tian, Ming et. al. “Growth Retardation, Early Death, and DNA Repair Defects in Mice Deficient for the Nucleotide Excision Repair Enzyme XPF.” Molecular and Cell Biology 24.3 (2004): 1200-1205. Brookman, Kerry W., et. al. “ERCC4 (XPF) Encodes a Human Nucleotide Excision Repair Protein with Eukaryotic Recombination Homologs.” Molecular and Cell Biology 16.11 (1996): 6553-6562. Lehmann, Alan R. “DNA repair-deficient diseases, xeroderma pigmentosum, Cokayne syndrome and trichothiodystrophy.” Biochimie 85.11 (2003): 1101-1111. Lodish, Harvey, et. al. Molecular and Cell Biology. 5 th ed. New York: W.H. Freeman and Company, 2004. Hall, Carl T. “Living in the Shadows.” San Francisco Chronicle 28 Nov 2004. Dimericine. 2006. AGIDermatics. 19 March 2006. < http://www.agiderm.com/ dimericine.php>