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 

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

NER in the cell 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 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 vol. 1. Macmillan Magazines Ltd.   stract.html?disname=Xeroderma%20Pigmentosu m stract.html?disname=Xeroderma%20Pigmentosu m   ples/Kramer.ppt#1 ples/Kramer.ppt#1  repair/euk-nucleotide-excision.html repair/euk-nucleotide-excision.html 

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