Cited by 548DNA Repair MechanismsGenetic and rare skin diseases.Genetic factors in colorectal cancer

Shining a light on xeroderma pigmentosum

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DiGiovanna, John J., Kraemer, Kenneth H.·2012·Journal of Investigative Dermatology

Abstract

Xeroderma pigmentosum (XP) is a rare, autosomal recessive disorder of DNA repair characterized by sun sensitivity and UV radiation-induced skin and mucous membrane cancers. Initially described in 1874 by Moriz Kaposi in Vienna, nearly 100 years later, James Cleaver in San Francisco reported defective DNA repair in XP cells. This eventually provided the basis for a mechanistic link between sun exposure, DNA damage, somatic mutations, and skin cancer. XP cells were found to have defects in seven of the proteins of the nucleotide excision repair pathway and in DNA polymerase η. XP cells are hypersensitive to killing by UV radiation, and XP cancers have characteristic "UV signature" mutations. Clinical studies at the National Institutes of Health found a nearly 10,000-fold increase in skin cancer in XP patients under the age of 20 years, demonstrating the substantial importance of DNA repair in cancer prevention in the general population. Approximately 25% of XP patients have progressive neurological degeneration with progressive loss of neurons, probably from DNA damage induced by oxidative metabolism, which kills nondividing cells in the nervous system. Interestingly, patients with another disorder, trichothiodystrophy, have defects in some of the same genes as XP, but they have primary developmental abnormalities without an increase in skin cancer.

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Crossref · 10.1038/jid.2011.426

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  • XP patients under the age of 20 years show a 10,000-fold increase in skin cancer, demonstrating the substantial importance of DNA repair in cancer prevention in the general population.

    “Specifically, XP patients under the age of 20 years show a 10,000-fold increase in skin cancer, which demonstrates the substantial importance of DNA repair in cancer prevention in the general population [203][204][205].”
  • Most xeroderma pigmentosum complementation groups A-G have a high incidence of skin tumors and deficiencies in nucleotide excision repair.

    “Another indirect evidence for the implication of photoinduced damage to DNA in carcinogenicity is provided by the high incidence of skin tumors in most of the complementation groups A-G of xeroderma pigmentosum patients (17,18) who suffer from deficiencies in nucleotide excision repair (19).”
  • XP patients, especially those with XPA deficiency, often suffer neurological deficiencies and an early-aging phenotype.

    “In addition to high dermatological sensitivity to sunlight XP patients, especially those with an XPA deficiency, often suffer from neurological deficiencies and an early-aging phenotype 2,”
  • The neurological and early-aging features of XPA deficiency are likely due to non-NER mechanisms.

    “likely due to non-NER mechanisms as exogenous, genotoxin-induced bulky adducts would not be a concern.”
  • NER is important for resistance to UV-induced cancers, as shown by XP patients with homozygous NER defects who are profoundly predisposed to melanoma and other UV-induced skin cancers.

    “The importance of NER in resistance to UV-induced cancers is clearly demonstrated by observing the natural history of xeroderma pigmentosum (XP) patients, who through homozygous loss of one of the enzymes that carry out NER, are profoundly predisposed to melanoma and other UV-induced skin cancers”

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Authors
DiGiovanna, J. J., & Kraemer, K. H.
Affiliations
National Cancer Institute (US)
Corresponding author
Kraemer, Kenneth H.
Venue
Journal of Investigative Dermatology
Publisher
Elsevier BV
Published
2012-03
Volume
132
Issue
3
Pages
785-796
ISSN
0022-202X (ISSN-L)
OpenAlex
W2082139407
Cited by
547
References
98
Citations by year
2026: 22 · 2025: 21 · 2024: 31 · 2023: 32 · 2022: 38 · 2021: 42 · 2020: 36 · 2019: 46 · 2018: 39 · 2017: 51 · 2016: 39 · 2015: 40 · 2014: 52 · 2013: 40 · 2012: 16
FWCI
4.32
Type
journal article
Language
en
Open access
Locations
  • Journal of Investigative Dermatology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (ZIABC004517)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
xeroderma pigmentosum, DNA repair, nucleotide excision repair, UV-induced skin cancer, sun sensitivity, neurodegeneration, trichothiodystrophy, cancer prevention
MeSH terms
DNA Repair, Humans, Skin Neoplasms, Sunlight, Xeroderma Pigmentosum

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