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!

Questions?