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XPF

XPF. Nucleotide Excision Repair. Xerderma Pigmentosum (XP). 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

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XPF

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  1. XPF Nucleotide Excision Repair

  2. Xerderma Pigmentosum (XP) • 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 pédagogiquehttp://www.inrp.fr/Acces/biotic/gpe/dossiers/xeroderma/html/phenomacr.htm

  3. XP: Complementation Groups • 8 subtypes identified by Cell-Fusion Complementation Tests • XPA-G : Nucleotide Excision Repair • XPV: DNA polymerase Sugasawa 2008

  4. UV Light and DNA Damage • cyclobutane pyrimidinedimer (CPD) (A) • pyrimidine -pyrimidone photoproduct (B) • bulky base adducts Sinha and Hӓder, 2002

  5. Nucleotide Excision Repair Sugasawa 2008

  6. 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

  7. Identification of cDNA of XPF • Cloned using rt-PCR fragment of Rad1 in a humantestis cDNA library • Encodes 115 kD protein • Chromosome 16p13.1–13.2 Sijbers et al.1996

  8. 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

  9. 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

  10. XPF in Humans • Majority of cases in Japan • Rare complementation group • Overall XP(all groups): 1 : 250,000 in US (Cleaver et al 1999)

  11. 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

  12. Future Directions • XPF role in homologous recombination • Its role outside of the NER complex

  13. 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

  14. QUESTONS?

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