Transcript Xeroderma Pigmentosum (XP)

Xeroderma Pigmentosum
(XPF)
Cara Mitchell
Characteristics of XP
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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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http://www.inrp.fr/Acces/biotic/gpe/dossiers/xeroderma/html/phenomacr.htm
Cause of XP
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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?
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Nucleotide
Excision Repair
Mechanism of
DNA repair
Used in repairing
UV damage
http://murray.francis.com/repair/3-UVcancer.htm
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
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7 main proteins involved in NER
Mutations are generally recessive
Mutations in XPA-G are
complementary
Different phenotypes possible
XP-F
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Milder phenotype
Later onset of cancers
Usually no neurological damage
Lessened photosensitivity
XPF Protein
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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)
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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
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XPF: endonuclease activity in NER
NER repairs UV damage to DNA
Dysfunctional NER
Buildup of mutations
Cancer
Protein Therapy
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Now in clinical trials
Introduces desired protein into cells
Uses viral proteins
Goes on via skin lotion!
Does not help neurological problems
Sources
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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
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http://www.rarediseases.org/search/rdbdetail_ab
stract.html?disname=Xeroderma%20Pigmentosu
m
http://www.xps.org/
http://www.bio.unc.edu/courses/Biology99/exam
ples/Kramer.ppt#1
http://www.cse.ucsc.edu/research/compbio/DNArepair/euk-nucleotide-excision.html
http://mcb.asm.org/cgi/content/full/24/3/1200
Thanks for Listening!
Questions?