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Xeroderma pigmentosum (XPF). Jennifer Lagasca March 4, 2003. What is XP?. Greek for “dry skin” (first case in 1870) inability to remove UV-induced damage from their DNA (1000 fold increased risk of cancer) autosomal recessive 16p13.1-13.2

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xeroderma pigmentosum xpf

Xeroderma pigmentosum (XPF)

Jennifer Lagasca

March 4, 2003

what is xp
What is XP?
  • Greek for “dry skin” (first case in 1870)
  • inability to remove UV-induced damage from their DNA (1000 fold increased risk of cancer)
  • autosomal recessive
  • 16p13.1-13.2
  • 7 complementation groups XPA-XPG (range in prevalence/severity)
  • prevalence (1:250000 US/Europe; 1:40000 Japan)
  • doesn’t discriminate
  • 1. Pigmentary changes (reddened/scale skin); irregular dark spots
  • 2. Poikiloderma-irregular patches of light and dark spots (spiderweb/thinning)
  • 3. Premature skin aging, dev. Of solar keratoses and skin cancers
  • other related symptoms: eye problems (lesions) (80%); neurological problems (20%)
  • XPF-mild phenotype USUALLY w/o neurological abnormalities
  • treatment

(Steeg et al. Molecular Medicine


uv damage and ner
UV damage and NER


review of ner
Review of NER
  • DNA damage recognition: XPC/HHR23B, XPA, XPE
  • DNA helix opening: XPB and XPD (helicases)
  • Dual incision: XPG (3’end) and XPF/ERCC1 (5’end)
  • Excision: DNA polymerase removes excised oligonucleotide
  • Gapfilling: DNA ligase fills gap by DNA synthesis
  • (www.rndsystems.com)
xpf ercc1 complex
XPF/ERCC1 complex

(Gaillard et al. Nucleic Acids Research. 2001)

  • XPF (103kDa) and ERCC1 (31kDa) incise at 22 nt to 5’
  • side of lesion
  • -N-terminal (DNA binding and endonuclease activity)
  • C-terminal (binds to ERCC1)-significant sequence similarity
Regions of Similarity Between XPF and ERCC1

(Gaillard et al. Nucleic Acids Research.2001)

isolation of human xpf with rad1
Isolation of human XPF with Rad1
  • S.cerevisiae (RAD1/RAD10 complex) -> cleave 5’ end
  • used primers (homology sequence) residues 699-758 (RT-PCR) - as probe
  • localized to 16p13.1-13.2
  • verified by complementation test -> injected isolated gene in nuclei of XPF pt.’s cells
  • cells irradiated with UV damage and radioactive letters
  • increased number of grains above the nuclei-> restored repair activity to normal level

(Sijbers et al. Cell.1996)

xpf and ercc1 are dependent of one another
XPF and ERCC1 are dependent of one another

(Yagi et al.


  • *anti-ERCC1 ab coimmunoprecipitated
  • a 120 kDa protein from normal cell
  • extract but not XPF cell extract (1997)
  • *low content of ERCC1 and 120 kDA
  • protein (frequent feature of XPF patients)
  • *transfected XP-F cDNA into mammalian vector plasmid -> XPFcells(1998)
  • *clone XP-FR2 -expressed high levels of ERCC1 and XPF (shows that ERCC1 is stabilized by binding to XPF)
r788 w mutation caucasian
R788 W Mutation (Caucasian)
  • 2nd Caucasian XPF patient (XP42RO)-late 40s w/ neurological symptoms (4-6 times reductions of NER activity)
  • Homozygous for point mutation in XPF (C->T at nuc.2377 changes arginine 788 to tryptophan
  • This mutation is leaky because a small amount of XPF could still be detected – still has repair activity-explains the mild phenotype
  • This same mutation was found in another Caucasian XP-F case; perhaps a Caucasian founder mutation?

Sijbers et al. The Journal of Investigative Dermatology.1998

mutations japanese cases
Mutations (Japanese cases)
  • 3 types of mutations: 1) aa subs, 2) aa/truncated, 3) truncated
  • N-terminal (homologous 86-333)-(XP101OS-heterozygous pt. mutation A-> G); all XPF cells have at least 1 normal allele in this region-suggests this is essential for basic cellular functioning
  • C-terminal (homologous 559-823)-ERCC1 binding domain
    • Mutations (XP3YO,XP2YO,XP1TS)
    • XP23OS lack this region- but still have XPF phenotype (mutation in C-terminal does not end NER function; supports that N-terminal (1-443) is important for process of NER)
  • XP24KY(truncated protein (no C-terminal) and protein with single aa subs (R443W)
    • Truncation probably not responsible for neurological disorders (XP23OS);R443W might
    • **mutations of XPF affecting C-terminal region-interfere with complex formation->rapid degradation of ERCC1
mutation spectrum of xpf
Mutation spectrum of XPF

(Matsumura et al. Human Molecular Genetics. 1998)

take home note
Take home note