Xeroderma pigmentosum xpf
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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.

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Characteristics of xp
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
Affected Individual

  • http://www.inrp.fr/Acces/biotic/gpe/dossiers/xeroderma/html/phenomacr.htm


Cause of xp
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
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
NER in the cell

Damage Recognition

Binding of protein complex

5’

3’

Incision of DNA

Oligonucleotide excision

DNA repair synthesis

http://egp.gs.washington.edu/ner.html


Complementation groups
Complementation Groups

  • 7 main proteins involved in NER

  • Mutations are generally recessive

  • Mutations in XPA-G are complementary

  • Different phenotypes possible


Xeroderma pigmentosum xpf
XP-F

  • Milder phenotype

  • Later onset of cancers

  • Usually no neurological damage

  • Lessened photosensitivity


Xpf protein
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
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

http://mcb.asm.org/cgi/content/full/24/3/1200


Back to the big picture
Back to the Big Picture

  • XPF: endonuclease activity in NER

  • NER repairs UV damage to DNA

  • Dysfunctional NER

    Buildup of mutations

    Cancer


Protein therapy
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
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