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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)

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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)

Xeroderma pigmentosum xpf

(Steeg et al.Molecular Medicine Today.1999)

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

Xeroderma pigmentosum xpf

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


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