Transcript Xeroderma Pigmentosum, XPF and Nucleotide Excision Repair

Xeroderma Pigmentosum, XPF
and Nucleotide Excision Repair
By Crystal Stanford
Xeroderma Pigmentosum (XP)
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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
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
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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
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UV damage to DNA
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UV light causes nucleotide bases to form ThymineThymine dimers
disrupt DNA synthesis and lead to mutations
Figure from Molecular Cell Biology (Lodish)
Nucleotide Excision Repair (NER)
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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
NER
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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
What is XPF?
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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
Mouse Knockouts
ERCC1 knockouts
 XPF: deficiency vs knockout
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Treatments & Studies
Prevention
 Gene therapy
 Dimericine (T4N5
Liposome Lotion)
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Figure from Dimericine website
References
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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. 5th ed. New York: W.H. Freeman
and Company, 2004.
Hall, Carl T. “Living in the Shadows.” San Francisco Chronicle 28 Nov 2004.
<www.sfgate.com>
Dimericine. 2006. AGIDermatics. 19 March 2006. <http://www.agiderm.com/
dimericine.php>