Download XPF

XPF
Nucleotide Excision Repair
Xerderma Pigmentosum (XP)
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UV Light Sensitivity
Early Age Freckling
Severe Sunburning
Keratosis
Neurological defects
Non-melonoma skin cancer ~10 yrs
basal and squamous cell carcinomas and
melanomas
• 1000x increase in risk of cancer
• autosomal recessive inheritance
• tumor suppressor
Image from: institut national de recherche pédagogique
http://www.inrp.fr/Acces/biotic/gpe/dossiers/xeroderma/html/phenomacr.htm
XP: Complementation Groups
• 8 subtypes identified by Cell-Fusion
Complementation Tests
• XPA-G : Nucleotide Excision Repair
• XPV: DNA polymerase
Sugasawa 2008
UV Light and DNA Damage
• cyclobutane pyrimidinedimer (CPD) (A)
• pyrimidine -pyrimidone photoproduct (B)
• bulky base adducts
Sinha and Hӓder, 2002
Nucleotide Excision Repair
Sugasawa 2008
ERCC1-XPF Complex
• XPF: 5’ endonuclease
• ERCC1: interacts with DNA through helix–
hairpin–helix (HhH) motif at C-terminus
• Only one recorded instance of human deficiency
• XPF Homologs:
– S. cerevisiae: Rad1
– Schizosaccharomyces pombe: rad16
– Drosophila melanogaster: MEI-9
– Mouse: ERCC4
Identification of cDNA of XPF
• Cloned using rtPCR fragment of
Rad1 in a human
testis cDNA
library
• Encodes 115 kD protein
• Chromosome 16p13.1–13.2
Sijbers et al.1996
5’ Endonuclease Activity
Chinese Hamster Cell Model
Shows ERCC1-XPF is
necessary for 5’ incisions that
only occur in coupled reactions
Sijbers et al.1996
Mouse Models
ERCC1 (-/-) Knockout Mice:
-died before weening
-liver failure
-kidney and vascular
defects
McWhir et al 1993
Reduced Function ERCC1 mice
-growth retardation
-lack of subcutaneous fat
-no similar symptoms of XP
-liver and vascular defects
Weeda et al 1997
XPF in Humans
• Majority of cases in Japan
• Rare complementation group
• Overall XP(all groups): 1 : 250,000 in US
(Cleaver et al 1999)
XP Treatments
• Palliative Care
• Avoidance of UV with frequent check ups
• Keratosis treatment with isotrentinoin
(prevention) and ctyotherapy and fluorouracil
• Applied Genetics, Inc.'s
– T4N5 endonuclease
study (Phase III)
– T4 endonuclease V
encapsulated in
liposome in cream
Future Directions
• XPF role in homologous recombination
• Its role outside of the NER complex
References
Cleaver, J. L. Thompson, A Richardson, and J. States. 1999. A Summary
of Mutations in the UV-Sensitive Disorders: Xeroderma Pigmentosum,
Cockayne Syndrome, and Trichothiodystrophy. Human Mutation. 14:9-22
de Laat W, AM. Sijbers, H. Odijk, Nicolaas GJ. Jaspers and J. Hoeijmakers.
1998. Mapping of interaction domains between human repairproteins
ERCC1 and XPF 1. Nuc. Acid Res. 26:4146-52
Sijber, A. A. de Laat, R. Ariza, M. Biggerstaff, YF. Wei, J. Moggs, K. Carter,
B. Shell, E. Evans, M. Jong, S. Rademakers, J. de Rooij, N. Jaspers, J.
Hoeijmakers, and R. Wooods. 1996. Xeroderma Pigmentosum Group F
Caused by a Defect in a Structure-Specific DNA Repair Endonuclease
Cell 86:811-22
Sinha, R. and D. Häder. 2002. UV-induced DNA damage and repair: a review.
Photochem. Photobiol. Sci. 1: 225-236
Sugasawa, K. 2008. Xeroderma pigmentosum genes: functions inside and
outside DNA repair. Carcinogenesis 29: 455-465.
Weeda, G. I. Donker, J. de Wit, H. Morreau, R. Janssens, C.J. Vissers, A.
Nigg, H. van Steeg, D. Bootsma and J.H.J. Hoeijmakers.1997. Disruption of
mouse ERCC1 results in a novel repair syndrome with growth failure,
nuclear abnormalities and senescence.Current Biology, 7:427–439
Xeroderma Pigmentosum. Updated 3/16/2008.
http://en.wikipedia.org/wiki/Xeroderma_pigmentosum
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